Diagnostic biomarker profiles for the detection and diagnosis of alzheimer&#39;s disease

ABSTRACT

The present invention provides methods, compositions and kits for the detection of Alzheimer&#39;s disease (AD) diagnostic biomarkers, for the diagnosis of AD, for the identification of a subject at risk for developing AD, and for the generation of patient-specific AD diagnostic biomarker profiles.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of, and claims priority to, U.S. patent application Ser. No. 14/232,347, filed Jul. 7, 2014, now allowed, which is a 35 U.S.C. § 371 U.S. National Phase of, and claims priority to, International Patent Application No. PCT/US2012/046502, filed Jul. 12, 2012, which claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Patent Application No. 61/507,006, filed Jul. 12, 2011, all of which are incorporated herein by reference in their entireties.

BACKGROUND OF THE INVENTION

Alzheimer's disease (AD) is a progressive and devastating neurodegenerative disorder of the elderly that is highlighted by a dramatic reduction of memory and cognition and linked to loss of neurons and synapses (Selkoe (2002) Science 298,789-791). Additional key pathological features include the deposition of amyloid beta (Aβ), especially the 42-amino acid peptide (Aβ42), within neurons, amyloid plaques and in the walls of brain blood vessels, as well as the appearance of neurofibrillary tangles, glial activation and widespread inflammation (Schwab et al. (2008) J. Alzheimers Dis 13, 359-369; Thal et al. (2008) Acta Neuropathol 115, 599-609; Weisman et al. (2006) Vitam Horm 74, 505-530). Aβ42 deposition within neurons is initiated early in the course of the disease, precedes amyloid plaque and tangle formation, and temporally and spatially coincides with loss of synapses in human AD and transgenic mouse brains (D'Andrea et al. (2001) Histopathology 38, 120-134; Nagele et al. (2002) Neuroscience 110, 199-211; Gouras et al. (2000) Am J. Pathol 156, 15-20).

Studies have reported the presence of immunoglobulin (Ig)-immunopositive neurons in histological sections of post-mortem AD brains, which were only rarely observed in comparable brain regions of non-demented, age-matched controls (Stein et al. (2002) J Neuropathol Exp Neurol 61, 1100-1108; Bouras et al. (2005) Brain Res Brain Res Rev 48, 477-487; D'Andrea (2003) Brain Res 982, 19-30). The presence of specific brain-reactive autoantibodies in the serum of AD patients has also been reported. (Bouras et al. (2005) Brain Res Brain Res Rev 48, 477-487; Kulmala et al. (1987) Exp Aging Res 13, 67-72; Mecocci et al. (1993) Biol Psychiatry 34, 380-385; Mecocci et al. (1995) J. Neuroimmunol 57, 165-170; Weksler et al. (2002) Exp Gerontol 37, 971-979).

BRIEF SUMMARY OF THE INVENTION

In one embodiment, the present invention provides a method for detecting AD diagnostic biomarkers in a subject in need of such detection comprising obtaining an immunoglobulin-containing biological sample from the subject, and performing an assay to determine the presence or absence of one or more AD diagnostic biomarkers in the biological sample.

In another embodiment, the present invention provides a method for diagnosing AD in a subject in need of such diagnosis comprising obtaining an immunoglobulin-containing biological sample from the subject, performing an assay to determine the presence or absence of one or more AD diagnostic biomarkers in the biological sample, and diagnosing AD if one or more AD diagnostic biomarkers are present.

In another embodiment, the present invention provides a method of identifying a subject at risk for developing a AD comprising obtaining an immunoglobulin-containing biological sample from the subject, performing an assay to determine the presence or absence of one or more AD diagnostic biomarkers in the biological sample, and identifying the subject as at risk for developing AD if one or more of the AD diagnostic biomarkers is present.

In another embodiment, the present invention provides a method of generating a patient-specific AD diagnostic biomarker profile comprising obtaining an immunoglobulin-containing biological sample from a patient, performing an assay to determine the presence or absence of one or more AD diagnostic biomarkers in the biological sample, and generating a patient-specific AD diagnostic biomarker profile of the AD diagnostic biomarkers present in the sample.

In yet another embodiment, the present invention provides a substrate on which one or more autoantigens that are specific for an AD diagnostic biomarker are immobilized.

The present invention provides, in another embodiment, a microarray comprising a substrate on which one or more autoantigens that are specific for an AD diagnostic biomarker are immobilized.

In a further embodiment, the present invention provides a kit for detecting AD-specific antibodies.

BRIEF DESCRIPTION OF THE DRAWINGS

The drawing displays a graphical representation of a diagnostic logic exemplified in Example 8.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the present invention, it has been discovered that brain-reactive autoantibodies are ubiquitous in the blood, and that these autoantibodies can enhance Aβ42 peptide deposition, a pathological hallmark of AD. It has further been discovered that brain-reactive autoantibodies are part of a much larger group of autoantibodies that are typically present in human sera, and that the expression of certain subsets of these autoantibodies is characteristically modulated by certain disease states such that disease-specific autoantibody patterns or profiles have been discovered and can be used as diagnostic biomarkers to detect and diagnose the presence of specific diseases such as AD. Among other embodiments, described herein is the use of these diagnostic biomarkers to accurately detect and diagnose AD based on their detection, identification and quantification revealed through interactions with their respective antigen targets on protein microarrays.

AD diagnostic biomarkers are defined herein as antibodies that specifically bind to protein antigens and are diagnostic indicators that can be used to differentiate Alzheimer's Disease from control subjects without AD. The term “protein antigens” as used herein includes protein and peptide antigens. Protein antigens that have been identified as capable of being specifically bound by the AD diagnostic biomarkers are set forth in the following Table 1. The protein antigens in Table 1 are identified by art-accepted names as well as database identification numbers. The database identification numbers refer to the publically available protein databases of the National Center for Biotechnology Information (NCBI), which are well-known and accessible to those of ordinary skill in the art.

TABLE 1 Database ID Description NM_024754.2 pentatricopeptide repeat domain 2 (PTCD2) BC051695.1 FERM domain containing 8 (FRMD8) NM_014280.1 DnaJ homolog subfamily C member 8 BC064984.1 additional sex combs like 1 (Drosophila) (ASXL1) NM_003384.1 vaccinia related kinase 1 (VRK1) NM_001544.2 intercellular adhesion molecule 4 (Landsteiner-Wiener blood group) (ICAM4), transcript variant 1 NM_001896.2 casein kinase 2, alpha prime polypeptide (CSNK2A2) NM_021104.1 ribosomal protein L41 (RPL41), transcript variant 1 BC016380.1 cDNA clone MGC: 27376 IMAGE: 4688477, complete cds NM_012387.1 peptidyl arginine deiminase, type IV (PADI4) NM_003135.1 Signal recognition particle 19 kDa protein BC022524.1 fibroblast growth factor 12 (FGF12) BC000758.1 Coiled-coil domain-containing protein 28A NM_021032.2 fibroblast growth factor 12 (FGF12), transcript variant 1 NM_022343.2 Golgi-associated plant pathogenesis-related protein 1 BC004236.2 ubiquitin-conjugating enzyme E25 (UBE2S) NM_000983.3 60S ribosomal protein L22 NM_017588.1 WD repeat domain 5 (WDR5), transcript variant 1 NM_018956.2 chromosome 9 open reading frame 9 (C9orf9) BC033178.1 immunoglobulin heavy constant gamma 3 (G3m marker) (IGHG3) NM_006628.4 cyclic AMP phosphoprotein, 19 kD (ARPP-19) BC022098.1 cDNA clone MGC: 31944 IMAGE: 4878869, complete cds NM_001641.2 APEX nuclease (multifunctional DNA repair enzyme) 1 (APEX1), transcript variant 1 NM_003668.2 mitogen-activated protein kinase-activated protein kinase 5 (MAPKAPK5), transcript variant 1 NM_015933.1 coiled-coil domain containing 72 (CCDC72) PHC1244 chemokine (C-C motif) ligand 19 (CCL19) BC007782.2 immunoglobulin lambda constant 1 (Mcg marker) (IGLC1) BC006423.1 Serine/threonine-protein kinase 6 BC042628.1 serpin peptidase inhibitor, clade E (nexin, plasminogen activator inhibitor type 1), member 2 (SERPINE2) BC021561.1 FACT complex subunit SPT16 BC005248.1 eukaryotic translation initiation factor 1A, Y-linked (EIF1AY) NM_006223.1 protein (peptidylprolyl cis/trans isomerase) NIMA-interacting, 4 (parvulin) (PIN4) NM_032377.2 elongation factor 1 homolog (S. cerevisiae) (ELOF1) BC057774.1 RNA (guanine-9-)-methyltransferase domain-containing protein 3 NM_004196.2 Cyclin-dependent kinase-like 1 BC001662.1 MAP kinase-activated protein kinase 3 NM_015920.3 40S ribosomal protein S27-like protein NM_001031.4 40S ribosomal protein S28 NM_003688.1 Peripheral plasma membrane protein CASK BC048970.1 tubulin tyrosine ligase-like family, member 7 (TTLL7) NM_000984.2 ribosomal protein L23a (RPL23A) NM_018439.1 Impact homolog (mouse) (IMPACT) NM_002305.2 lectin, galactoside-binding, soluble, 1 (galectin 1) (LGALS1) BC056508.1 variable charge, Y-linked 1B (VCY) BC090938.1 Ig gamma-1 chain C region NM_002013.2 FK506 binding protein 3, 25 kDa (FKBP3) NM_007278.1 GABA(A) receptor-associated protein (GABARAP) BC007228.1 CSAG family, member 3A (CSAG3A) BC033758.1 centaurin, alpha 2 (CENTA2) BC092518.1 Ig gamma-1 chain C region BC019598.1 Zinc finger matrin-type protein 4 NM_145909.1 Zinc finger protein 323 NM_003516.2 histone cluster 2, H2aa3 (HIST2H2AA3) NM_006838.1 methionyl aminopeptidase 2 (METAP2) BC026038.1 Ig gamma-1 chain C region NM_002129.2 high-mobility group box 2 (HMGB2) NM_002677.1 peripheral myelin protein 2 (PMP2) BC001132.1 DEAD (Asp-Glu-Ala-Asp) box polypeptide 54 (DDX54) NM_001001794.1 family with sequence similarity 116, member B (FAM116B) NM_001997.2 Finkel-Biskis-Reilly murine sarcoma virus (FBR-MuSV) ubiquitously expressed (FAU) BC021174.1 Small EDRK-rich factor 1 NM_001028.2 ribosomal protein S25 (RP525) NM_003512.3 Histone H2A type 1-C NM_002095.1 general transcription factor IIE, polypeptide 2, beta 34 kDa (GTF2E2) NM_005720.1 actin related protein 2/3 complex, subunit 1B, 41 kDa (ARPC1B) NM_003868.1 fibroblast growth factor 16 (FGF16) NM_004214.3 fibroblast growth factor (acidic) intracellular binding protein (FIBP), transcript variant 2 NM_021079.2 N-myristoyltransferase 1 (NMT1) NM_015833.1 adenosine deaminase, RNA-specific, B1 (RED1 homolog rat) (ADARB1), transcript variant 2 PHR5001 Recombinant human CTLA-4/Fc BC030983.1 immunoglobulin lambda locus (IGL@) BC030984.1 cDNA clone MGC: 32654 IMAGE: 4701898, complete cds NM_133494.1 NIMA (never in mitosis gene a)- related kinase 7 (NEK7) BC010467.1 cDNA clone MGC: 17410 IMAGE: 4156035, complete cds NM_014060.1 malignant T cell amplified sequence 1 (MCTS1) NM_016167.3 nucleolar protein 7, 27 kDa (NOL7) BC015833.1 cDNA clone MGC: 27152 IMAGE: 4691630, complete cds NM_145063.1 chromosome 6 open reading frame 130 (C6orf130) BC040106.1 hypothetical protein HSPC111 (HSPC111) BC010947.1 signal recognition particle 19 kDa (SRP19) NM_014065.2 Protein asteroid homolog 1 BC012760.2 Glycogen synthase kinase-3 beta NM_004088.1 deoxynucleotidyltransferase, terminal (DNTT), transcript variant 1 BC019337.1 immunoglobulin heavy constant gamma 1 (G1m marker) (IGHG1) NM_002938.2 ring finger protein 4 (RNF4) NM_006620.2 HBS1-like (S. cerevisiae) (HBS1L) NM_000992.2 60S ribosomal protein L29 NM_024668.2 ankyrin repeat and KH domain containing 1 (ANKHD1), transcript variant 3 NM_031445.1 AMME chromosomal region gene 1-like (AMMECR1L) NM_003517.2 histone cluster 2, H2ac (HIST2H2AC) BC072419.1 Ig gamma-1 chain C region NM_145174.1 DnaJ (Hsp40) homolog, subfamily B, member 7 (DNAJB7) BC022361.1 rRNA-processing protein FCF1 homolog BC006376.1 N-myristoyltransferase 2 (NMT2) NM_001895.1 casein kinase 2, alpha 1 polypeptide (C5NK2A1), transcript variant 2 NM_003524.2 Histone H2B type 1-H BC027951.1 Cas scaffolding protein family member 4 NM_134427.1 regulator of G-protein signaling 3 (RGS3), transcript variant 4 NM_052969.1 ribosomal protein L39-like (RPL39L) NM_023080.1 chromosome 8 open reading frame 33 (C8orf33) NM_138779.1 chromosome 13 open reading frame 27 (C13orf27) BC026030.1 zinc finger protein 239 (ZNF239) BC029760.1 OTU domain containing 6B (OTUD6B) PHC1475 C-C motif chemokine 21 NM_133336.1 Wolf-Hirschhorn syndrome candidate 1 (WHSC1), transcript variant 9 BC034142.1 immunoglobulin kappa variable 1-5 (IGKV1-5) NM_020235.2 bobby sox homolog (Drosophila) (BBX) NM_198829.1 Ras-related C3 botulinum toxin substrate 1 BC098112.1 Histone H2B type 1-N NM_032359.1 chromosome 3 open reading frame 26 (C3orf26) NM_001966.2 Peroxi somal bifunctional enzyme BC032451.1 cDNA clone MGC: 40426 IMAGE: 5178085, complete cds XM_379117.1 PREDICTED: Homo sapiens hypothetical protein L0C150568 (LOC150568) BC033159.1 DnaJ (Hsp40) homolog, subfamily C, member 8 (DNAJC8) NM_006756.2 transcription elongation factor A (SII), 1 (TCEA1), transcript variant 1 NM_016940.1 RWD domain containing 2B (RWDD2B) NM_177559.2 casein kinase 2, alpha 1 polypeptide (CSNK2A1), transcript variant 1 NM_004178.3 TAR (HIV-1) RNA binding protein 2 (TARBP2), transcript variant 3 NM_032338.2 chromosome 12 open reading frame 31 (C12orf31) BC005955.1 chromosome 8 open reading frame 53 (C8orf53) NM_001009613.1 Sperm protein associated with the nucleus on the X chromosome N4 BC036723.1 Fc fragment of IgG, low affinity Ma, receptor (CD16a) (FCGR3A) NM_003690.3 Interferon-inducible double stranded RNA-dependent protein kinase activator A NM_014473.2 DIM1 dimethyladenosine transferase 1-like (S. cerevisiae) (DIMT1L) NM_032855.1 hematopoietic 5H2 domain containing (HSH2D) NM_001167.2 baculoviral IAP repeat-containing 4 (BIRC4) NM_178571.2 hypothetical protein MGC51025 (MGC51025) NM_003600.1 aurora kinase A (AURKA), transcript variant 2 NM_006912.3 Ras-like without CAAX 1 (RIT1) NM_005307.1 G protein-coupled receptor kinase 4 BC001280.1 Serine/threonine-protein kinase 6 NM_182970.2 regulating synaptic membrane exocytosis 4 (RIMS4) NM_153332.2 three prime histone mRNA exonuclease 1 (THEX1) NM_139016.2 chromosome 20 open reading frame 198 (C20orf198) NM_003677.3 Density-regulated protein NM_013293.1 Transformer-2 protein homolog BC033856.1 La ribonucleoprotein domain family, member 1 (LARP1) NM_000939.1 proopiomelanocortin (adrenocorticotropin/beta-lipotropin/ alpha-melanocyte stimulating hormone/beta-melanocyte stimulating hormone/ beta-endorphin) (POMC), transcript variant 2 BC009348.2 cirrhosis, autosomal recessive 1A (cirhin) (CIRH1A) NM_014508.2 apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3C (APOBEC3C), mRNA. NM_080659.1 chromosome 11 open reading frame 52 (C11orf52) NM_022755.2 inositol 1,3,4,5,6-pentakisphosphate 2-kinase (IPPK) NM_002690.1 polymerase (DNA directed), beta (POLB) BC011668.1 Casein kinase II subunit alpha NM_002128.2 high-mobility group box 1 (HMGB1) BC012472.1 ubiquitin D (UBD) BC030020.2 DEAD (Asp-Glu-Ala-Asp) box polypeptide 55 (DDX55) BC018060.1 Ras-like without CAAX 2 (RIT2) NM_003141.2 tripartite motif-containing 21 (TRIM21) NM_007054.1 kinesin family member 3A (KIF3A) NM_006924.3 splicing factor, arginine/serine-rich 1 (splicing factor 2, alternate splicing factor) (SFRS1), transcript variant 1 NM_032563.1 late cornified envelope 3D (LCE3D) NM_173080.1 small proline-rich protein 4 (SPRR4) NM_003527.4 Histone H2B type 1-O BC009762.2 Tripartite motif-containing protein 41 NM_006861.2 RAB35, member RAS oncogene family (RAB35) NM_002136.1 heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1), transcript variant 1 BC009623.1 nucleophosmin (nucleolar phosphoprotein B23, numatrin) (NPM1) NM_021063.2 Histone H2B type 1-D BC054021.1 pterin-4 alpha-carbinolamine dehydratase/dimerization cofactor of hepatocyte nuclear factor 1 alpha (TCF1) 2 (PCBD2) NM_012108.1 signal transducing adaptor family member 1 (STAP1) NM_023937.1 mitochondrial ribosomal protein L34 (MRPL34), nuclear gene encoding mitochondrial protein XM_088679.2 Spermatid nuclear transition protein 4 NM_022720.5 DiGeorge syndrome critical region gene 8 (DGCR8) NM_016073.2 hepatoma-derived growth factor, related protein 3 (HDGFRP3) NM_018105.1 THAP domain containing, apoptosis associated protein 1 (THAP1), transcript variant 1 NM_005371.2 methyltransferase like 1 (METTL1), transcript variant 1 BC029427.1 coiled-coil domain containing 23 (CCDC23) NM_032476.1 mitochondrial ribosomal protein S6 (MRPS6), nuclear gene encoding mitochondrial protein NM_003089.4 small nuclear ribonucleoprotein 70 kDa polypeptide (RNP antigen) (SNRP70) BC020972.1 Casein kinase I isoform gamma-2 BC000381.2 TBP-like 1 (TBPL1) NM_007285.5 GABA(A) receptor-associated protein-like 2 (GABARAPL2) NM_004060.2 cyclin G1 (CCNG1), transcript variant 1 BC001780.1 Uncharacterized methyltransferase WBSCR22 NM_022048.1 casein kinase 1, gamma 1 (CSNK1G1) BC035256.1 Putative adenylate kinase 7 NM_175887.2 proline rich 15 (PRR15) BC010919.1 ribosomal protein L35 (RPL35) NM_016207.2 cleavage and polyadenylation specific factor 3, 73 kDa (CPSF3) BC000784.1 baculoviral IAP repeat-containing 5 (survivin) (BIRC5) NM_002364.1 melanoma antigen family B, 2 (MAGEB2) NM_022839.2 mitochondrial ribosomal protein S11 (MRPS11), nuclear gene encoding mitochondrial protein, transcript variant 1 NM_014370.2 SFRS protein kinase 3 (SRPK3) NM_016505.2 zinc finger, CCHC domain containing 17 (ZCCHC17) BC030813.1 cDNA clone MGC: 22645 IMAGE: 4700961, complete cds BC020803.1 developmentally regulated GTP binding protein 1 (DRG1) NM_205848.1 synaptotagmin VI (SYT6) NM_006398.2 Ubiquitin D NM_017646.3 tRNA isopentenyltransferase 1 (TRIT1) NM_006925.2 Splicing factor, arginine/serine-rich 5 NM_153822.1 proteasome (prosome, macropain) 26S subunit, non-ATPase, 4 (PSMD4), transcript variant 2 NM_014321.2 origin recognition complex, subunit 6 like (yeast) (ORC6L) BC012876.1 Ig lambda chain C regions NM_021967.1 small EDRK-rich factor 1A (telomeric) (SERF1A) NM_003295.1 tumor protein, translationally-controlled 1 (TPT1) NM_017503.2 surfeit 2 (SURF2) BC018137.1 TATA box binding protein (TBP)-associated factor, RNA polymerase I, B, 63 kDa (TAF1B) BC005004.1 family with sequence similarity 64, member A (FAM64A) NM_152373.2 zinc finger protein 684 (ZNF684) NM_000989.2 ribosomal protein L30 (RPL30) NM_000800.2 fibroblast growth factor 1 (acidic) (FGF1), transcript variant 1 NM_000975.2 ribosomal protein L11 (RPL11) PHC1695 C-X-C motif chemokine 11 NM_022140.2 Band 4.1-like protein 4A NM_016287.2 heterochromatin protein 1, binding protein 3 (HP1BP3) BC015586.2 laminin, gamma 1 (formerly LAMB2) (LAMC1) NM_023931.1 zinc finger protein 747 (ZNF747) NM_153207.2 AE binding protein 2 (AEBP2) NM_007079.2 Protein tyrosine phosphatase type IVA 3 NM_004397.3 Probable ATP-dependent RNA helicase DDX6 NM_012424.2 Ribosomal protein S6 kinase delta-1 NM_020239.2 CDC42 small effector 1 (CDC42SE1), transcript variant 2 BC029378.1 telomeric repeat binding factor (NIMA-interacting) 1 (TERF1) BC000306.1 hydroxyacyl-Coenzyme A dehydrogenase (HADH) NM_182692.1 Serine/threonine-protein kinase SRPK2 NM_032350.3 Uncharacterized protein C7orf50 NM_001022.3 ribosomal protein S19 (RPS19) NM_001002913.1 peptidyl-tRNA hydrolase 1 homolog (S. cerevisiae) (PTRH1) BC000535.1 Suppressor of SWI4 1 homolog NM_017692.1 aprataxin (APTX), transcript variant 4 NM_000993.2 ribosomal protein L31 (RPL31), transcript variant 1 NM_152653.1 ubiquitin-conjugating enzyme E2E 2 (UBC4/5 homolog, yeast) (UBE2E2) NM_014891.1 PDGFA associated protein 1 (PDAP1) NM_012148.1 double homeobox, 3 (DUX3) NM_024046.1 CaM kinase-like vesicle-associated (CAMKV) NM_022063.1 chromosome 10 open reading frame 84 (C10orf4) BC036434.1 Serine/threonine-protein kinase VRK2 NM_001396.2 Dual specificity tyrosine-phosphorylation-regulated kinase 1A NM_004939.1 DEAD (Asp-Glu-Ala-Asp) box polypeptide 1 (DDX1) NM_001039724.1 Nostrin NM_138551.1 thymic stromal lymphopoietin (TSLP), transcript variant 2 XM_379194.1 PREDICTED: Homo sapiens hypothetical LOC401068 (LOC401068) BC007401.2 cell division cycle 25 homolog A (S. pombe) (CDC25A) BC008902.2 GRIP and coiled-coil domain-containing protein 1 BC019039.2 Regulator of G-protein signaling 3 NM_016050.1 mitochondrial ribosomal protein L11 (MRPL11), nuclear gene encoding mitochondrial protein, transcript variant 1 NM_002927.3 regulator of G-protein signaling 13 (RGS13), transcript variant 1 NM_207430.1 FLJ46266 protein (FLJ46266), mRNA. NM_016508.2 Cyclin-dependent kinase-like 3 NM_197964.1 chromosome 7 open reading frame 55 (C7orf55) BC021930.1 KIAA1530 protein (KIAA1530) NM_145043.1 nei like 2 (E. coli) (NEIL2) BC030586.2 signal transducing adaptor molecule (SH3 domain and ITAM motif) 1 (STAM) BC004292.1 PHD finger protein 15 (PHF15) BC022378.1 zinc finger with KRAB and SCAN domains 1 (ZKSCAN1) NM_003792.1 endothelial differentiation-related factor 1 (EDF1), transcript variant alpha BC070154.1 Non-histone chromosomal protein HMG-14 BC010074.2 FUS interacting protein (serine/arginine-rich) 1 (FUSIP1) NM_002201.3 interferon stimulated exonuclease gene 20 kDa (ISG20) BC033621.2 Pseudouridylate synthase 7 homolog-like protein NM_004114.2 fibroblast growth factor 13 (FGF13), transcript variant 1A NM_012420.1 interferon-induced protein with tetratricopeptide repeats 5 (IFIT5) NM_016203.2 protein kinase, AMP-activated, gamma 2 non-catalytic subunit (PRKAG2), transcript variant a, mRNA. NM_014878.2 Pumilio domain-containing protein KIAA0020 NM_018664.1 Jun dimerization protein p21SNFT (SNFT) NM_002402.1 mesoderm specific transcript homolog (mouse) (MEST), transcript variant 1 NM_003769.2 splicing factor, arginine/serine-rich 9 (SFRS9) NM_018132.3 centromere protein Q (CENPQ) NM_006072.4 chemokine (C-C motif) ligand 26 (CCL26) NM_021029.3 ribosomal protein L36a (RPL36A) NM_000978.2 ribosomal protein L23 (RPL23) NM_001023.2 ribosomal protein S20 (RPS20) BC013366.2 UNC-112 related protein 2 (URP2) BC001327.1 interferon-related developmental regulator 2 (IFRD2) BC000522.1 serpin peptidase inhibitor, clade F (alpha-2 antiplasmin, pigment epithelium derived factor), member 1 (SERPINF1) NM_019067.1 guanine nucleotide binding protein-like 3 (nucleolar)-like (GNL3L) NM_152634.1 TFS2-M domain-containing protein 1 (MGC17403) BC011842.2 hypothetical protein FLJ11184 (FLJ11184) BC068514.1 NF-kappaB repressing factor (NKRF) NM_018063.3 helicase, lymphoid-specific (HELLS) NM_198467.1 round spermatid basic protein 1-like (RSBN1L) NM_198517.2 TBC1 domain family, member 10C (TBC1D10C) NM_001564.1 inhibitor of growth family, member 2 (ING2) NM_002930.1 GTP-binding protein Rit2 NM_019058.1 DNA-damage-inducible transcript 4 protein NM_020661.1 activation-induced cytidine deaminase (AICDA) NM_173822.1 family with sequence similarity 126, member B (FAM126B) BC056887.1 chromosome 5 open reading frame 5 (C5orf5) BC070334.1 immunoglobulin kappa constant (IGKC) NM_004071.1 Dual specificity protein kinase CLK1 NM_005801.2 eukaryotic translation initiation factor 1 (EIF1) BC001487.2 TAR DNA-binding protein 43 NM_006790.1 myotilin (MYOT) NM_175923.2 hypothetical protein MGC42630 (MGC42630) NM_000122.1 excision repair cross-complementing rodent repair deficiency, complementation group 3 (xeroderma pigmentosum group B complementing) (ERCC3) BC010501.1 Catenin delta-1 BC005298.1 cyclin-dependent kinase 7 (M015 homolog, Xenopus laevis, cdk-activating kinase) (CDK7) PHC0076 interleukin 7 (IL7) NM_138349.2 Tumor protein p53-inducible protein 13 BC000044.1 Spindlin-2B NM_014747.2 regulating synaptic membrane exocytosis 3 (RIMS3) NM_001014.2 ribosomal protein S10 (RPS10) NM_005678.3 SNRPN upstream reading frame (SNURF), transcript variant 1 BC010876.1 nei endonuclease VIII-like 1 (E. coli) (NEIL1) BC025281.1 RNA binding motif protein 9 (RBM9) NM_001013.2 ribosomal protein S9 (RPS9) NM_015414.2 ribosomal protein L36 (RPL36), transcript variant 2 NM_017566.2 kelch domain containing 4 (KLHDC4) BC015818.1 lectin, galactoside-binding, soluble, 8 (galectin 8) (LGALS8) BC036109.1 SECTS binding protein 2 (SECISBP2) NM_005738.1 ADP-ribosylation factor-like 4A (ARL4A), transcript variant 1 BC022816.1 NA NM_024303.1 zinc finger and SCAN domain containing 5 (ZSCAN5) BC018823.2 splicing factor, arginine/serine-rich 5 (SFRS5) NM_024319.1 chromosome 1 open reading frame 35 (C1orf35) PV3359 Ephrin receptor A3 (EPHA3), transcript variant 1 NM_145899.1 high mobility group AT-hook 1 (HMGA1), transcript variant 1 NM_021158.1 tribbles homolog 3 (Drosophila) (TRIB3) NM_005794.2 dehydrogenase/reductase (SDR family) member 2 (DHRS2), transcript variant 2 BC005807.2 stearoyl-CoA desaturase (delta-9-desaturase) (SCD) NM_006374.2 serine/threonine kinase 25 (STE20 homolog, yeast) (5TK25) NM_152757.1 Putative uncharacterized protein C20orf200 NM_001009880.1 chromosome 22 open reading frame 9 (C22orP9), transcript variant 2 NM_138558.1 protein phosphatase 1, regulatory (inhibitor) subunit 8 (PPP1R8), transcript variant 2 BC007852.1 Serine/threonine-protein kinase 25 NM_012396.1 pleckstrin homology-like domain, family A, member 3 (PHLDA3) NM_012437.2 SNAP-associated protein (SNAPAP) PHC0205 interleukin 20 (IL20) NM_016093.2 ribosomal protein L26-like 1 (RPL26L1) NM_005902.1 SMAD family member 3 (SMAD3) XM_375456.2 Ataxin-7-like protein 3 NM_006275.2 splicing factor, arginine/serine-rich 6 (SFRS6) BC011600.1 cDNA clone IMAGE: 3050953, **** WARNING: chimeric clone **** NM_014570.2 ADP-ribosylation factor GTPase activating protein 3 (ARFGAP3) NM_022551.2 ribosomal protein S18 (RPS18) BC063275.1 eukaryotic translation initiation factor 2C, 1 (EIF2C1) BC062423.1 chromosome 7 open reading frame 41 (C7orf41) BC096708.1 Wilms tumor-associated protein NM_199123.1 SET domain containing 3 (SETD3), transcript variant 2 BC010907.1 PAK1 interacting protein 1 (PAK1IP1) NM_004217.1 aurora kinase B (AURKB) NM_005737.3 ADP-ribosylation factor-like 4C (ARL4C) NM_020467.2 small trans-membrane and glycosylated protein (L0057228), transcript variant 2 BC021180.2 high-mobility group box 4 (HMGB4) NM_004728.2 DEAD (Asp-Glu-Ala-Asp) box polypeptide 21 (DDX21) BC030702.1 microcephaly, primary autosomal recessive 1 (MCPH1) NM_003724.1 jerky homolog (mouse) (JRK), transcript variant 1 NM_016077.1 peptidyl-tRNA hydrolase 2 (PTRH2), nuclear gene encoding mitochondrial protein NM_014955.2 KIAA0859 (KIAA0859), transcript variant 2 NM_003503.2 Cell division cycle 7-related protein kinase BC017212.2 PHD finger protein 11 (PHF11) NM_019069.3 WD repeat domain 5B (WDR5B) BC094719.1 Rho GTPase-activating protein 12 BC021187.1 DKFZP434K028 protein (DKFZP434K028) NM_003948.2 Cyclin-dependent kinase-like 2 BC040183.2 Rap guanine nucleotide exchange factor (GEF) 4 (RAPGEF4) NM_014061.3 melanoma antigen family H, 1 (MAGEH1) BC032587.1 tubby like protein 3 (TULP3) BC005332.1 cDNA clone MGC: 12418 IMAGE: 3934658, complete cds BC033710.2 RAD54 homolog B (S. cerevisiae) (RAD54B) BC010425.1 acyl-Coenzyme A oxidase 1, palmitoyl (ACOX1) NM_021138.2 TNF receptor-associated factor 2 (TRAF2) BC093990.1 Sin3 histone deacetylase corepressor complex component 5D53 NM_014288.2 Centromere protein R NM_024826.1 Microtubule-associated protein 9 BC035968.1 chloride intracellular channel 5 (CLIC5) BC096165.1 Troponin I, cardiac muscle BC012105.1 nuclear VCP-like (NVL) BC011924.1 unkempt homolog (Drosophila)-like (UNKL) NM_001311.2 Cysteine-rich protein 1 NM_014445.2 stress-associated endoplasmic reticulum protein 1 (SERPI) NM_005979.1 S100 calcium binding protein A13 (S100A13), transcript variant 2 BC036923.1 chromosome 9 open reading frame 150 (C9orf150) NM_033671.1 cyclin B3 (CCNB3), transcript variant 2 BC014441.1 NOL1/NOP2/Sun domain family, member 4 (NSUN4) BC031549.1 CDC-like kinase 1 (CLK1) NM_194290.1 cDNA FLJ42001 fis, clone SPLEN2029912 (LOC153684 protein) [Source: UniProtKB/TrEMBL; Acc: Q6ZVW3] BC053984.1 immunoglobulin heavy variable 4-31 (IGHV4-31) BC050563.1 hypothetical protein LOC202051 (LOC202051) BC050718.1 polymerase (DNA directed) kappa (POLK) BC000896.1 RAB10, member RAS oncogene family (RAB10) NM_006252.2 AMP-activated protein_kinase A2/B1/G1: PRKAA2/B1/G1 sequences are seperated by -- (in protein list file). BC013630.1 JTV1 gene (JTV1) BC009108.1 cDNA clone IMAGE: 3451214 (MCM10) BC002645.1 syntaxin 5 (STX5) NM_138414.1 coiled-coil domain containing 101 (CCDC101) NM_002740.1 protein kinase C, iota (PRKCI) NM_002822.3 twinfilin, actin-binding protein, homolog 1 (Drosophila) (TWF1) BC003566.1 zinc finger protein 24 (ZNF24) NM_022756.2 Uncharacterized protein C1orf149 NM_153035.1 chromosome 1 open reading frame 83 (C1orf83) NM_177524.1 mesoderm specific transcript homolog (mouse) (MEST), transcript variant 2 NM_004635.2 mitogen-activated protein kinase-activated protein kinase 3 (MAPKAPK3) NM_005607.1 Focal adhesion kinase 1 BC010697.1 RNA-binding protein 40 NM_174942.1 GAS2-like protein 3 BC038976.1 Rho GTPase-activating protein 15 NM_012117.1 chromobox homolog 5 (HP1 alpha homolog, Drosophila) (CBX5) NM_013313.3 yippee-like 1 (Drosophila) (YPEL1) NM_148179.1 chromosome 9 open reading frame 23 (C9orf23), transcript variant 2 BC038105.2 membrane protein, palmitoylated 7 (MAGUK p55 subfamily member 7) (MPP7) BC091489.1 zinc finger, MYND domain containing 11, mRNA (cDNA clone MGC: 111056 IMAGE: 6186814), complete cds BC034435.1 zinc finger CCCH-type containing 3 (ZC3H3) NM_152736.2 Zinc finger protein 187 NM_015014.1 RNA binding motif protein 34 (RBM34) NM_003137.2 SFRS protein kinase 1 (SRPK1) BC016486.1 lectin, galactoside-binding, soluble, 8 (galectin 8) (LGALS8) BC000238.1 ankyrin repeat and zinc finger domain containing 1 (ANKZF1) NM_002904.4 RD RNA binding protein (RDBP) BC009046.1 neurogenic differentiation 1 (NEUROD1) NM_198965.1 Parathyroid hormone-related protein BC047776.2 coiled-coil domain containing 43 (CCDC43) NM_001004306.1 similar to hypothetical protein FLJ36492 (MGC87631) NM_006800.2 male-specific lethal 3-like 1 (Drosophila) (MSL3L1), transcript variant 3 NM_006038.1 spermatogenesis associated 2 (SPATA2) NM_014477.2 chromosome 20 open reading frame 10 (C20orf10) BC027612.2 EP300-interacting inhibitor of differentiation 3 NM_017411.2 survival of motor neuron 2, centromeric (SMN2), transcript variant d BC004876.1 Protein MCM10 homolog NM_201516.1 H2A histone family, member V (H2AFV), transcript variant 4 NM_022156.3 dihydrouridine synthase 1-like (S. cerevisiae) (DUS1L) BC015742.1 polymerase (DNA directed), eta (POLH) NM_001015509.1 Peptidyl-tRNA hydrolase 2, mitochondrial NM_014366.1 guanine nucleotide binding protein-like 3 (nucleolar) (GNL3), transcript variant 1 NM_018357.2 La ribonucleoprotein domain family, member 6 (LARP6), transcript variant 1 BC020221.1 SH3 and cysteine rich domain (STAC) NM_005307.1 G protein-coupled receptor kinase 4 NM_017785.2 coiled-coil domain containing 99 (CCDC99) BC026101.2 nudE nuclear distribution gene E homolog (A. nidulans)-like 1 (NDEL1) NM_175571.2 GTPase, IMAP family member 8 (GIMAP8) NM_004286.2 GTP binding protein 1 (GTPBP1) BC072461.1 Cysteine and histidine-rich domain-containing protein 1 BC047945.1 tripartite motif-containing 69 (TRIM69) BC005858.1 fibronectin 1 (FN1) NM_001722.2 polymerase (RNA) III (DNA directed) polypeptide D, 44 kDa (POLR3D) NM_024333.1 Fibronectin type III and SPRY domain-containing protein 1 NM_144595.1 SLAIN motif family, member 1 (SLAIN1), transcript variant 2 NM_002469.1 myogenic factor 6 (herculin) (MYF6) BC053866.1 endothelin 3 (EDN3) NM_001319.5 casein kinase 1, gamma 2 (CSNK1G2) BC006124.1 IMP (inosine monophosphate) dehydrogenase 2 (IMPDH2) NM_014667.1 vestigial like 4 (Drosophila) (VGLL4) NM_031465.2 chromosome 12 open reading frame 32 (C12orf32) NM_182612.1 Parkinson disease 7 domain containing 1 (PDDC1) PV4803 epidermal growth factor receptor (erythroblastic leukemia viral (v- erb-b) oncogene homolog, avian) (EGFR); see catalog number for detailed information on wild-type or point mutant status NM_152266.1 chromosome 19 open reading frame 40 (C19orf40) NM_000997.2 ribosomal protein L37 (RPL37) BC001728.1 TCF3 fusion partner BC007015.1 cyclin E2 (CCNE2) NM_022347.1 interferon responsive gene 15 (IFRG15) BC031821.1 Secernin-3 NM_016304.2 chromosome 15 open reading frame 15 (C15orf15) BC069677.1 Regulator of G-protein signaling 8 BC013331.1 H2A histone family, member Y (H2AFY) NM_017838.2 nucleolar protein family A, member 2 (H/ACA small nucleolar RNPs) (NOLA2), transcript variant 1 BC013796.1 adaptor-related protein complex 2, mu 1 subunit (AP2M1) NM_080743.2 serine-arginine repressor protein (35 kDa) (SRrp35) BC000190.1 zinc finger, C3HC-type containing 1 (ZC3HC1) BC036089.1 myeloid/lymphoid or mixed-lineage leukemia (trithorax homolog, Drosophila); translocated to, 3 (MLLT3) NM_018215.2 hypothetical protein FLJ10781 (FLJ10781), transcript variant 1 BC095401.1 AKT-interacting protein NM_001008572.1 tubulin tyrosine ligase-like family, member 1 (TTLL1), transcript variant 2 BC103812.1 Alpha-ketoglutarate-dependent dioxygenase alkB homolog 3 BC036365.1 PH domain-containing protein C10or81 NM_016047.1 splicing factor 3B, 14 kDa subunit (SF3B14) BC014949.1 DEXH (Asp-Glu-X-His) box polypeptide 58 (DHX58) BC047690.1 Ras-related protein M-Ras NM_001894.2 casein kinase 1, epsilon (CSNK1E), transcript variant 2 NM_006482.1 Dual specificity tyrosine-phosphorylation-regulated kinase 2 NM_025104.2 Protein DBF4 homolog B NM_017819.1 RNA (guanine-9-)-methyltransferase domain-containing protein 1, mitochondrial NM_199139.1 XIAP associated factor-1 (XAF1), transcript variant 2 NM_003910.2 BUD31 homolog (S. cerevisiae) (BUD31) BC000442.1 Serine/threonine-protein kinase 12 BC028711.2 cancer/testis antigen CT45-3 (CT45-3) NM_018158.1 solute carrier family 4 (anion exchanger), member 1, adaptor protein (SLC4A1AP) BC034692.1 anillin, actin binding protein (ANLN) NM_173605.1 potassium channel regulator (KCNRG), transcript variant 1 NM_014047.1 chromosome 19 open reading frame 53 (C19orf53) BC073791.1 immunoglobulin kappa constant, mRNA (cDNA clone MGC: 88809 IMAGE: 6279986), complete cds BC014928.1 MYC-induced nuclear antigen BC053656.1 EGF-like repeats and discoidin I-like domains 3 (EDIL3) XM_378879.2 PREDICTED: Homo sapiens hypothetical LOC400763 (LOC400763) NM_017817.1 RAB20, member RAS oncogene family (RAB20) BC031608.1 REST corepressor 3 (RCOR3) BC047722.1 hypothetical protein MGC52110 (MGC52110) BC020726.1 sciellin (SCEL) NM_024039.1 MIS12, MIND kinetochore complex component, homolog (yeast) (MIS12) BC026213.1 F-box/WD repeat-containing protein 11 NM_002135.3 nuclear receptor subfamily 4, group A, member 1 (NR4A1), transcript variant 1 NM_015939.2 tRNA methyltransferase 6 homolog (S. cerevisiae) (TRMT6) NM_018039.2 jumonji domain containing 2D (JMJD2D) NM_007373.2 soc-2 suppressor of clear homolog (C. elegans) (SHOC2) BC067120.1 protein tyrosine phosphatase domain containing 1, mRNA (cDNA clone MGC: 70358 IMAGE: 5539182), complete cds NM_015918.2 processing of precursor 5, ribonuclease P/MRP subunit (S. cerevisiae) (POPS), transcript variant 1 NM_152677.1 zinc finger and SCAN domain containing 4 (ZSCAN4) BC008902.2 GRIP and coiled-coil domain-containing protein 1 NM_001008239.1 chromosome 18 open reading frame 25 (C18orf25), transcript variant 2 NM_183397.1 peroxisomal membrane protein 4, 24 kDa (PXMP4), transcript variant 2 NM_006337.3 microspherule protein 1 (MCRS1), transcript variant 1 BC034401.1 cDNA clone IMAGE: 5172086, partial cds NM_006755.1 transaldolase 1 (TALDO1) NM_004853.1 syntaxin 8 (STX8) BC036910.1 hypothetical LOC388882 (LOC388882) BC094687.1 Elongation factor 1-alpha 1 NM_144608.1 hexamthylene bis-acetamide inducible 2 (HEXIM2) NM_003831.1 RIO kinase 3 (yeast) (RIOK3) BC009250.1 guanine nucleotide binding protein-like 2 (nucleolar) (GNL2) BC032598.1 NHL repeat containing 2 (NHLRC2) NM_018697.3 LanC lantibiotic synthetase component C-like 2 (bacterial) (LANCL2) NM_024104.1 chromosome 19 open reading frame 42 (C19orf42) BC030665.1 Sulfotransferase 4A1 BC004955.1 ATPase inhibitory factor 1 (ATPIF1) BC009010.1 Uncharacterized protein C6orf142 homolog BC012887.1 Nucleolar and spindle-associated protein 1 BC015066.1 core-binding factor, runt domain, alpha subunit 2; translocated to, 2 (CBFA2T2) BC052303.1 Rho GTPase activating protein 4 (ARHGAP4) NM_080414.1 vacuolar protein sorting 16 homolog (S. cerevisiae) (VPS16), transcript variant 2 NM_001790.2 cell division cycle 25 homolog C (S. pombe) (CDC25C), transcript variant 1 PHC0045 interleukin 4 (IL4), transcript variant 1 NM_145041.1 transmembrane protein 106A (TMEM106A) NM_021639.2 GC-rich promoter binding protein 1-like 1 (GPBP1L1) BC028295.1 peptidase D (PEPD) PV3612 aurora kinase A (AURKA), transcript variant 2 NM_032321.1 hypothetical protein MGC13057 (MGC13057), transcript variant 4 BC010033.1 quinolinate phosphoribosyltransferase (nicotinate-nucleotide pyrophosphorylase (carboxylating)) (QPRT) NM_001064.1 Transketolase NM_017572.2 MAP kinase-interacting serine/threonine-protein kinase 2 NM_022650.1 RAS p21 protein activator (GTPase activating protein) 1 (RASA1), transcript variant 2 NM_020781.2 zinc finger protein 398 (ZNF398), transcript variant 2 NM_002391.1 midkine (neurite growth-promoting factor 2) (MDK), transcript variant 3 NM_006298.2 zinc finger protein 192 (ZNF192) BC047536.1 sciellin (SCEL) NM_139062.1 casein kinase 1, delta (CSNK1D), transcript variant 2 NM_005639.1 synaptotagmin I (SYT1) BC006811.1 peroxisome proliferator-activated receptor gamma (PPARG) BC008364.1 heterogeneous nuclear ribonucleoprotein C (C1/C2) (HNRPC) NM_032345.1 within bgcn homolog (Drosophila) (WIBG) BC016825.1 spire homolog 1 (Drosophila) (SPIRE1) NM_020664.3 2,4-dienoyl CoA reductase 2, peroxisomal (DECR2) NM_017542.3 pogo transposable element with KRAB domain (POGK) NM_003160.1 Serine/threonine-protein kinase 13 BC026346.1 family with sequence similarity 84, member A (FAM84A) BC041037.1 immunoglobulin heavy constant mu (IGHM) BC033677.1 Uncharacterized protein C9orf114 BC055427.1 TRAF2 and NCK interacting kinase (TNIK) NM_016648.1 La ribonucleoprotein domain family, member 7 (LARP7), transcript variant 1 BC064145.1 CDK5 regulatory subunit associated protein 1-like 1 (CDKAL1) NM_138565.1 cortactin (CTTN), transcript variant 2 NM_022823.1 fibronectin type III domain containing 4 (FNDC4) BC006104.1 RIO kinase 1 (yeast) (RIOK1) BC014975.1 family with sequence similarity 136, member A (FAM136A) NM_138730.1 high mobility group nucleosomal binding domain 3 (HMGN3), transcript variant 2 NM_025004.1 Coiled-coil domain-containing protein 15 NM_004092.2 Enoyl-CoA hydratase, mitochondrial NM_021107.1 mitochondrial ribosomal protein S12 (MRPS12), nuclear gene encoding mitochondrial protein, transcript variant 1 NM_053049.2 Urocortin-3 NM_001545.1 immature colon carcinoma transcript 1 (ICT1) NM_148571.1 mitochondrial ribosomal protein L27 (MRPL27), nuclear gene encoding mitochondrial protein, transcript variant 2 NM_001003799.1 TCR gamma alternate reading frame protein (TARP), nuclear gene encoding mitochondrial protein, transcript variant 1 BC017227.1 phosducin-like (PDCL) NM_172159.2 potassium voltage-gated channel, shaker-related subfamily, beta member 1 (KCNAB1), transcript variant 3 NM_000462.2 ubiquitin protein ligase E3A (human papilloma virus E6-associated protein, Angelman syndrome) (UBE3A), transcript variant 2 XM_210860.4 PREDICTED: Homo sapiens hypothetical LOC283034 (LOC283034) BC022344.1 twinfilin, actin-binding protein, homolog 1 (Drosophila) (TWF1) NM_005037.3 peroxisome proliferator-activated receptor gamma (PPARG), transcript variant 4 NM_022977.1 acyl-CoA synthetase long-chain family member 4 (ACSL4), transcript variant 2 NM_006217.2 serpin peptidase inhibitor, clade I (pancpin), member 2 (SERPINI2) NM_024979.2 Guanine nucleotide exchange factor DBS NM_016286.1 dicarbonyl/L-xylulose reductase (DCXR) NM_003160.1 Serine/threonine-protein kinase 13 NM_015687.2 filamin A interacting protein 1 (FILIP1) BC005871.2 chromosome 10 open reading frame 58 (C10orf58) NM_016216.2 Lariat debranching enzyme NM_017856.1 gem (nuclear organelle) associated protein 8 (GEMIN8), transcript variant 3 NM_015869.2 peroxisome proliferator-activated receptor gamma (PPARG), transcript variant 2 NM_001003397.1 Tumor protein D53 NM_001018061.1 UPF0544 protein C5orf45 [Source: UniProtKB/Swiss- Prot; Acc: Q6NTE8] BC013900.1 chromosome 12 open reading frame 41 (C12orf41) BC022988.1 chromosome 6 open reading frame 65 (C6orf65) NM_006299.2 zinc finger protein 193 (ZNF193) BC018847.1 Transaldolase NM_139355.1 megakaryocyte-associated tyrosine kinase (MATK), transcript variant 1 NM_207356.1 chromosome 1 open reading frame 174 (C1orf174) NM_001008737.1 hypothetical LOC401052 (LOC401052) NM_145109.1 mitogen-activated protein kinase kinase 3 (MAP2K3), transcript variant B BC017114.1 oligonucleotide/oligosaccharide-binding fold containing 2A (OBFC2A) XM_086879.4 PREDICTED: Homo sapiens hypothetical LOC150371 (LOC150371) NM_078630.1 male-specific lethal 3-like 1 (Drosophila) (MSL3L1), transcript variant 2 NM_005197.2 Forkhead box protein N3 NM_004602.2 Double-stranded RNA-binding protein Staufen homolog 1 BC017504.1 Differentially expressed in FDCP 6 homolog NM_003590.2 cullin 3 (CUL3) NM_145702.1 tigger transposable element derived 1 (TIGD1) BC001935.1 cyclin-dependent kinase inhibitor 1A (p21, Cip1) (CDKN1A) NM_004965.3 high-mobility group nucleosome binding domain 1 (HMGN1) BC032508.1 PNMA-like 1, mRNA (cDNA clone MGC: 45422 IMAGE: 5246377), complete cds BC013966.2 family with sequence similarity 64, member A (FAM64A) NM_020236.2 mitochondrial ribosomal protein Ll (MRPL1), nuclear gene encoding mitochondrial protein BC043247.2 transducin-like enhancer of split 3 (E(sp1) homolog, Drosophila) (TLE3) BC057806.1 insulin-like growth factor binding protein 1 (IGFBP1) NM_006573.2 tumor necrosis factor (ligand) superfamily, member 13b (TNFSF13B) BC025406.1 phosphodiesterase 4D interacting protein (myomegalin) (PDE4DIP) BC002559.1 YTH domain family, member 2 (YTHDF2) NM_052926.1 Paraneoplastic antigen-like protein 5 NM_006254.3 protein kinase C, delta (PRKCD), transcript variant 1 BC022003.1 myotubularin related protein 9 (MTMR9) BC043348.2 retinitis pigmentosa 2 (X-linked recessive) (RP2) NM_018010.2 intraflagellar transport 57 homolog (Chlamydomonas) (IFT57) BC044851.1 vacuolar protein sorting 41 homolog (S. cerevisiae) (VPS41) BC068094.1 5H3 domain and tetratricopeptide repeats 1 (SH3TC1) NM_020961.2 KIAA1627 protein (KIAA1627) PV3757 myosin light chain kinase 2, skeletal muscle (MYLK2) NM_002451.3 methylthioadenosine phosphorylase (MTAP), mRNA. NM_000281.1 pterin-4 alpha-carbinolamine dehydratase/dimerization cofactor of hepatocyte nuclear factor 1 alpha (TCF1) (PCBD1) NM_144982.1 coiled-coil domain containing 131 (CCDC131) NM_017927.2 mitofusin 1 (MFN1), nuclear gene encoding mitochondrial protein, transcript variant 2 NM_002150.1 4-hydroxyphenylpyruvate dioxygenase NM_016267.1 vestigial like 1 (Drosophila) (VGLL1) BC067299.1 Mdm4, transformed 3T3 cell double minute 4, p53 binding protein (mouse) (MDM4) XM_378988.2 PREDICTED: Homo sapiens hypothetical LOC400849 (LOC400849) NM_006466.1 polymerase (RNA) III (DNA directed) polypeptide F, 39 kDa (POLR3F) BC042608.1 family with sequence similarity 90, member A1 (FAM90A1) NM_025136.1 optic atrophy 3 (autosomal recessive, with chorea and spastic paraplegia) (OPA3), transcript variant 2 BC012620.1 golgi SNAP receptor complex member 1 (GOSR1) NM_139244.2 syntaxin binding protein 5 (tomosyn) (STXBP5) NM_015929.2 lipoyltransferase 1 (LIPT1), transcript variant 1 PV3366 v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived oncogene homolog (avian) (ERBB2), transcript variant 2 NM_133629.1 RAD51-like 3 (S. cerevisiae) (RAD51L3), transcript variant 4 XM_294794.1 PREDICTED: Homo sapiens similar to putative membrane-bound dipeptidase 2 (LOC339065) BC012289.1 K1AA0515 (K1AA0515) BC029444.1 immunoglobulin kappa constant (IGKC) BC015109.1 39S ribosomal protein Ll, mitochondrial NM_024578.1 occludin/ELL domain containing 1 (OCEL1) NM_003908.1 eukaryotic translation initiation factor 2, subunit 2 beta, 38 kDa (EIF2S2) BC001726.1 Nucleolar protein 11 BC003666.2 NAD synthetase 1 (NADSYN1) NM_198491.1 family with sequence similarity 92, member B (FAM92B) PV3817 WEE1 homolog (S. pombe) (WEE1) BC000974.2 WDR45-like (WDR45L) BC053675.1 thymopoietin (TMPO) BC033292.1 interleukin 20 receptor beta (IL20RB) BC002509.1 PHD finger protein 23 BC006969.1 dynein, cytoplasmic 2, light intermediate chain 1, mRNA (cDNA clone MGC: 12166 IMAGE: 3828551), complete cds BC069491.1 Cerberus NM_138559.1 B-cell CLL/lymphoma 11A (zinc finger protein) (BCL11A), transcript variant 3 BC004376.1 annexin A8 (ANXA8L1) NM_005620.1 S100 calcium binding protein A11 (S100A11) PV3872 epidermal growth factor receptor (erythroblastic leukemia viral (v- erb-b) oncogene homolog, avian) (EGFR); see catalog number for detailed information on wild-type or point mutant status NM_032214.1 Src-like-adaptor 2 (SLA2), transcript variant 1 NM_002444.1 moesin (MSN) NM_173796.2 hypothetical protein MGC24125 (MGC24125) NM_002648.1 pim-1 oncogene (PIM1) NM_001876.2 Carnitine O-palmitoyltransferase 1, liver isoform BC014532.1 decapping enzyme, scavenger (DCPS) NM_001005266.1 Dresden prostate carcinoma protein 2 NM_007172.2 nucleoporin 50 kDa (NUP50), transcript variant 2 NM_018326.1 GTPase, IMAP family member 4 (GIMAP4) BC033881.1 XRCC6 binding protein 1 (XRCC6BP1) NM_020168.3 p21(CDKN1A)-activated kinase 6 (PAK6) NM_014790.3 janus kinase and microtubule interacting protein 2 (JAKMIP2) NM_032360.1 acyl-Coenzyme A binding domain containing 6 (ACBD6) NM_006303.2 JTV1 gene (JTV1) BC017305.1 sirtuin (silent mating type information regulation 2 homolog) 7 (S. cerevisiae) (SIRT7) BC051762.1 Uncharacterized protein C20orf96 NM_145010.1 chromosome 10 open reading frame 63 (C10orf63) NM_206834.1 Uncharacterized protein C6orf201 BC009350.1 Eukaryotic translation initiation factor 2-alpha kinase 4 NM_003720.1 Proteasome assembly chaperone 1 BC067755.1 potassium channel tetramerisation domain containing 18 (KCTD18) BC005840.2 selenoprotein S (SELS) BC000934.2 eukaryotic translation initiation factor 2, subunit 2 beta, 38 kDa (EIF2S2) NM_020175.1 dihydrouridine synthase 3-like (S. cerevisiae) (DUS3L) BC014667.1 immunoglobulin heavy constant gamma 1 (G1m marker) (IGHG1) NM_201403.1 MOB1, Mps One Binder kinase activator-like 2C (yeast) (MOBKL2C), transcript variant 2 BC010537.1 SUB1 homolog (S. cerevisiae) (SUB1) NM_170746.2 Selenoprotein H NM_003092.3 small nuclear ribonucleoprotein polypeptide B″ (SNRPB2), transcript variant 1 NM_005105.2 RNA binding motif protein 8A (RBM8A) BC047411.1 tubulin tyrosine ligase-like family, member 2 (TTLL2) NM_199188.1 La ribonucleoprotein domain family, member 4 (LARP4), transcript variant 2 BC003551.1 transglutaminase 2 (C polypeptide, protein-glutamine-gamma- glutamyltransferase) (TGM2) BC020647.1 coiled-coil domain containing 59 (CCDC59) BC011781.2 chromosome 9 open reading frame 37 (C9orf37) NM_032858.1 maelstrom homolog (Drosophila) (MAEL) NM_144971.1 hypothetical protein MGC26641 (MGC26641) BC017440.1 trafficking protein particle complex 2-like (TRAPPC2L) BC017018.1 DnaJ (Hsp40) homolog, subfamily C, member 12 (DNAJC12) NM_144767.3 A kinase (PRKA) anchor protein 13 (AKAP13), transcript variant 3 NM_018297.2 N-glycanase 1 (NGLY1) NM_002307.1 lectin, galactoside-binding, soluble, 7 (galectin 7) (LGALS7) NM_003939.2 beta-transducin repeat containing (BTRC), transcript variant 2, mRNA. NM_013242.1 chromosome 16 open reading frame 80 (C16orf80) NM_152285.1 arrestin domain containing 1 (ARRDC1) NM_178425.1 histone deacetylase 9 (HDAC9), transcript variant 5 NM_007255.1 xylosylprotein beta 1,4-galactosyltransferase, polypeptide 7 (galactosyltransferase I) (B4GALT7) NM_205833.1 immunoglobulin superfamily, member 1 (IGSF1), transcript variant 2 BC040457.1 calcium/calmodulin-dependent protein kinase (CaM kinase) II alpha (CAMK2A) NM_004732.1 potassium voltage-gated channel, shaker-related subfamily, beta member 3 (KCNAB3) NM_004450.1 enhancer of rudimentary homolog (Drosophila) (ERH) XM_378582.2 PREDICTED: Homo sapiens hypothetical LOC400523 (LOC400523) NM_001006666.1 apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3F (APOBEC3F), transcript variant 2, mRNA. BC041876.1 tau tubulin kinase 2 (TTBK2) BC036335.1 BTB (POZ) domain containing 12 (BTBD12) BC036099.1 aryl-hydrocarbon receptor nuclear translocator 2 (ARNT2) NM_054012.1 argininosuccinate synthetase 1 (ASS1), transcript variant 2 NM_057749.1 cyclin E2 (CCNE2) PV3839 CDC-like kinase 4 (CLK4) BC005026.1 sirtuin (silent mating type information regulation 2 homolog) 6 (S. cerevisiae) (SIRT6) NM_013975.1 ligase III, DNA, ATP-dependent (LIG3), nuclear gene encoding mitochondrial protein, transcript variant alpha NM_181509.1 microtubule-associated protein 1 light chain 3 alpha (MAP1LC3A), transcript variant 2 BC001709.1 NAD kinase (NADK) NM_002638.1 peptidase inhibitor 3, skin-derived (SKALP) (PI3) NM_005901.2 SMAD family member 2 (SMAD2), transcript variant 1 BC046199.1 family with sequence similarity 72, member B (FAM72B) NM_015417.2 sperm flagellar 1 (SPEF1) NM_018328.1 methyl-CpG binding domain protein 5 (MBD5) BC017328.2 angiotensin II receptor-associated protein (AGTRAP) NM_182739.1 NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 6, 17 kDa (NDUFB6), nuclear gene encoding mitochondrial protein, transcript variant 2 NM_001032293.1 zinc finger protein 207 (ZNF207), transcript variant 2 NM_012227.1 Putative GTP-binding protein 6 BC026039.1 mitochondrial GTPase 1 homolog (S. cerevisiae) (MTG1) BC072409.1 Serine/threonine-protein phosphatase 4 regulatory subunit 3A BC066938.1 DEAD (Asp-Glu-Ala-Asp) box polypeptide 43 (DDX43) BC000712.1 kinesin family member C1 (KIFC1) BC000052.1 peroxisome proliferator-activated receptor alpha (PPARA) NM_004117.2 FK506 binding protein 5 (FKBP5) NM_002629.2 phosphoglycerate mutase 1 (brain) (PGAM1) NM_015122.1 FCH domain only 1 (FCHO1) NM_001021.2 ribosomal protein S17 (RPS17) NM_013323.1 sorting nexin 11 (SNX11), transcript variant 2 BC002950.1 chromosome 18 open reading frame 8 (C18orf8) NM_017612.1 Zinc finger CCHC domain-containing protein 8 BC035048.2 neurogenic differentiation 6 (NEUROD6) BC046117.1 dynein, axonemal, light intermediate chain 1 (DNALI1) NM_005335.3 Hematopoietic lineage cell-specific protein NM_144679.1 chromosome 17 open reading frame 56 (C17orf56) NM_004881.1 tumor protein p53 inducible protein 3 (TP53I3), transcript variant 1 NM_199334.2 thyroid hormone receptor, alpha (erythroblastic leukemia viral (v- erb-a) oncogene homolog, avian) (THRA), transcript variant 1 NM_201567.1 cell division cycle 25 homolog A (S. pombe) (CDC25A), transcript variant 2 BC012945.1 Uncharacterized protein Cl9orf57 BC043394.1 ankyrin repeat domain 17 (ANKRD17) NM_053005.2 HCCA2 protein (HCCA2) NM_175065.2 histone cluster 2, H2ab (HIST2H2AB) NM_004706.3 Rho guanine nucleotide exchange factor (GEF) 1 (ARHGEF1), transcript variant 2 NM_014346.1 TBC1 domain family, member 22A (TBC1D22A) NM_133480.1 transcriptional adaptor 3 (NGG1 homolog, yeast)-like (TADA3L), transcript variant 2 BC048969.1 TSPY-like 1 (TSPYL1) NM_020319.1 ankyrin repeat and MYND domain containing 2 (ANKMY2) NM_016046.2 exosome component 1 (EXOSC1) NM_001003396.1 tumor protein D52-like 1 (TPD52L1), transcript variant 3 NM_005870.3 Histone deacetylase complex subunit SAP18 NM_003403.3 YY1 transcription factor (YY1) BC036096.2 zinc finger protein 18 (ZNF18) NM_001010844.1 Interleukin-1 receptor-associated kinase 1-binding protein 1 BC029524.1 Coiled-coil domain-containing protein 46 NM_152387.2 BTB/POZ domain-containing protein KCTD18 BC002369.1 Serine/threonine-protein kinase PLK1 BC092404.1 Rap guanine nucleotide exchange factor 3 NM_004922.2 SEC24 related gene family, member C (S. cerevisiae) (SEC24C), transcript variant 1 NM_198217.1 Inhibitor of growth protein 1 BC051911.1 chromosome 13 open reading frame 24 (C13orf24) NM_006205.1 phosphodiesterase 6H, cGMP-specific, cone, gamma (PDE6H) NM_006439.3 Protein mab-21-like 2 NM_173456.1 phosphodiesterase 8A (PDE8A), transcript variant 4 BC019268.1 Protein arginine N-methyltransferase 1 NM_173642.1 family with sequence similarity 80, member A (FAM80A) NM_194299.1 Synaptonemal complex protein 2-like BC062323.1 chromosome 21 open reading frame 25 (C21orf25) NM_021709.1 Apoptosis regulatory protein Siva BC100813.1 Putative T-complex protein 1 subunit theta-like 2 BC026317.1 solute carrier family 16, member 1 (monocarboxylic acid transporter 1) (SLC16A1) BC010956.1 Keratinocyte growth factor NM_005034.2 polymerase (RNA) II (DNA directed) polypeptide K, 7.0 kDa (POLR2K) BC024291.1 BR serine/threonine kinase 2 (BRSK2) NM_001001568.1 phosphodiesterase 9A (PDE9A), transcript variant 3, mRNA. NM_014314.3 Probable ATP-dependent RNA helicase DDX58 BC047420.1 UBX domain-containing protein 7 NM_000430.2 platelet-activating factor acetylhydrolase, isoform Ib, alpha subunit 45 kDa (PAFAH1B1) PV3873 epidermal growth factor receptor (erythroblastic leukemia viral (v- erb-b) oncogene homolog, avian) (EGFR); see catalog number for detailed information on wild-type or point mutant status NM_001328.1 C-terminal binding protein 1 (CTBP1), transcript variant 1 NM_001009959.1 Ermin BC050387.1 ankyrin repeat and sterile alpha motif domain containing 3 (ANKS3) NM_007194.1 Serine/threonine-protein kinase Chk2 NM_018492.2 PDZ binding kinase (PBK) NM_182801.1 EGF-like, fibronectin type III and laminin G domains (EGFLAM), transcript variant 4 BC016615.1 RAB37, member RAS oncogene family (RAB37) BC008950.2 Prenylated Rab acceptor protein 1 BC041831.1 transducin-like enhancer of split 3 (E(sp1) homolog, Drosophila) (TLE3) NM_003104.2 sorbitol dehydrogenase (SORD) BC003555.1 nucleolar complex associated 2 homolog (S. cerevisiae) (NOC2L) NM_001274.2 CHK1 checkpoint homolog (S. pombe) (CHEK1) NM_153645.1 nucleoporin 50 kDa (NUP50), transcript variant 3 BC017423.1 mesoderm induction early response 1 homolog (Xenopus laevis) (MIER1) BC007424.2 PRP4 pre-mRNA processing factor 4 homolog (yeast) (PRPF4) NM_007107.2 signal sequence receptor, gamma (translocon-associated protein gamma) (55R3) XM_096472.2 hypothetical LOC143678 (LOC143678) NM_015698.2 G patch domain and KOW motifs (GPKOW) NM_018111.1 Putative uncharacterized protein FLJ10490 NM_006694.1 jumping translocation breakpoint (JTB) NM_000045.2 arginase, liver (ARG1) BC074765.2 POU domain, class 6, transcription factor 1 NM_172028.1 ankyrin repeat and BTB (POZ) domain containing 1 (ABTB1), transcript variant 3 BC026345.1 Ermin NM_201262.1 DnaJ (Hsp40) homolog, subfamily C, member 12 (DNAJC12), transcript variant 2 NM_002966.1 S100 calcium binding protein A10 (S100A10) BC013352.1 HpaII tiny fragments locus 9c protein NM_004873.1 BCL2-associated athanogene 5 (BAGS), transcript variant 2 BC009415.1 kinesin family member 26A (KIF26A) BC012539.1 mediator complex subunit 31 (MED31) BC021247.1 Phosphatase and actin regulator 4 NM_004414.3 regulator of calcineurin 1 (RCAN1), transcript variant 1 BC028840.1 ankyrin repeat domain 13C (ANKRD13C) BC025787.1 alkB, alkylation repair homolog 1 (E. coli) (ALKBH1) NM_000459.1 Angiopoietin-1 receptor NM_000788.1 Deoxycytidine kinase NM_173859.1 breast cancer and salivary gland expression gene (RP11-49G10.8) NM_152382.1 JmjC domain-containing protein C2orf60 NM_002038.2 interferon, alpha-inducible protein 6 (IFI6), transcript variant 1 BC034984.1 Kinesin-like protein KIF16B NM_014582.1 odorant binding protein 2A (OBP2A) BC057760.1 MORN repeat-containing protein 3 NM_005595.1 nuclear factor I/A (NFIA) NM_032726.1 phospholipase C, delta 4 (PLCD4) NM_153276.1 solute carrier family 22 (organic anion transporter), member 6 (SLC22A6), transcript variant 2 NM_001011538.1 similar to 60S ribosomal protein L21 (LOC402176) NM_006433.2 granulysin (GNLY), transcript variant NKG5 NM_024800.1 Serine/threonine-protein kinase Nek11 NM_015850.2 Basic fibroblast growth factor receptor 1 NM_006590.2 ubiquitin specific peptidase 39 (USP39) NM_199054.1 MAP kinase interacting serine/threonine kinase 2 (MKNK2), transcript variant 2 BC050696.1 chromosome 12 open reading frame 48 (C12orf48) NM_024563.1 chromosome 5 open reading frame 23 (C5orf23) NM_004832.1 glutathione S-transferase omega 1 (GSTO1) NM_003242.2 transforming growth factor, beta receptor II (70/80 kDa) (TGFBR2), transcript variant 2 BC050444.1 golgi autoantigen, golgin subfamily a, 4 (GOLGA4) NM_201259.1 Mitochondrial import inner membrane translocase subunit TIM14 NM_032124.3 haloacid dehalogenase-like hydrolase domain containing 2 (HDHD2) NM_002870.1 RAB13, member RAS oncogene family (RAB13) BC000337.2 glucose-6-phosphate dehydrogenase (G6PD) BC060785.1 tripartite motif-containing 40 (TRIM40) BC030597.1 ATR interacting protein (TREX1) BC050551.1 BCL2-associated athanogene 5 (BAGS) NM_004697.3 PRP4 pre-mRNA processing factor 4 homolog (yeast) (PRPF4) NM_020990.2 creatine kinase, mitochondrial 1B (CKMT1B), nuclear gene encoding mitochondrial protein BC039742.1 poly(rC) binding protein 1 (PCBP1) BC021573.1 GTP-binding protein 10 NM_015068.1 paternally expressed 10 (PEG10), transcript variant 1 NM_001827.1 CDC28 protein kinase regulatory subunit 2 (CKS2) NM_152876.1 Tumor necrosis factor receptor superfamily member 6 BC015548.1 RAB3A interacting protein (rabin3) (RAB3IP) BC062359.1 chromosome 8 open reading frame 47 (C8orf47) BC029424.1 Probable glutathione peroxidase 8 NM_001786.2 cell division cycle 2, G1 to S and G2 to M (CDC2), transcript variant 1 BC000870.1 TIMELESS interacting protein (TIPIN) NM_004103.2 Protein tyrosine kinase 2 beta BC022454.2 Transient receptor potential cation channel subfamily M member 3 NM_024046.1 CaM kinase-like vesicle-associated (CAMKV) BC040521.1 testis expressed 2 (TEX2) BC003164.1 leukocyte receptor cluster (LRC) member 4 (LENG4) NM_000402.2 Glucose-6-phosphate 1-dehydrogenase BC069328.1 Bcl2 modifying factor (BMF) BC063463.1 coenzyme Q3 homolog, methyltransferase (S. cerevisiae) (COQ3) NM_000572.2 Interleukin-10 NM_006374.2 serine/threonine kinase 25 (STE20 homolog, yeast) (STK25) NM_017966.1 vacuolar protein sorting 37 homolog C (S. cerevisiae) (VPS37C) BC052602.1 carbonic anhydrase XIII (CA13) BC018063.1 potassium channel tetramerisation domain containing 4 (KCTD4) NM_031305.1 Rho GTPase activating protein 24 (ARHGAP24), transcript variant 2 BC056401.1 centaurin, delta 2 (CENTD2) BC022459.1 sulfotransferase family 4A, member 1 (SULT4A1) XM_373630.2 PREDICTED: Homo sapiens hypothetical protein LOC145842 (LOC145842) P3049 v-abl Abelson murine leukemia viral oncogene homolog 1 (ABL1), transcript variant a; see catalog number for detailed information on wild-type or point mutant status NM_153012.1 Tumor necrosis factor ligand superfamily member 12 NM_018270.3 MRG-binding protein BC010739.1 COP9 signalosome complex subunit 7b NM_015002.2 F-box protein 21 (FBXO21), transcript variant 2 BC000497.1 CaM kinase-like vesicle-associated protein NM_001449.2 four and a half LIM domains 1 (FHL1) BC065912.1 Tyrosine-protein kinase ABL2 NM_153356.1 TBC1 domain family, member 21 (TBC1D21) BC032382.1 similar to pleckstrin homology domain containing, family M (with RUN domain) member 1; adapter protein 162, mRNA, complete cds. BC094800.1 Jouberin NM_003897.2 immediate early response 3 (IER3) NM_178821.1 WD repeat domain 69 (WDR69) NM_198219.1 Inhibitor of growth protein 1 NM_024805.1 chromosome 18 open reading frame 22 (C18orf22) NM_001040633.1 protein kinase, AMP-activated, gamma 2 non-catalytic subunit (PRKAG2), transcript variant c, mRNA. NM_130807.1 MOB1, Mps One Binder kinase activator-like 2A (yeast) (MOBKL2A) BC008623.1 roundabout, axon guidance receptor, homolog 3 (Drosophila) (ROBO3) NM_001004285.1 DNA fragmentation factor, 40 kDa, beta polypeptide (caspase- activated DNase) (DFFB), transcript variant 3 BC011885.1 eukaryotic translation initiation factor 2A, 65 kDa (EIF2A)

Thus in one embodiment, the present invention provides a method for detecting AD diagnostic biomarkers in a subject in need of such detection comprising obtaining an immunoglobulin-containing biological sample from the subject, and performing an assay to determine the presence or absence of one or more AD diagnostic biomarkers in the biological sample.

In another embodiment, the present invention provides a method for diagnosing Alzheimer's Disease (AD) in a subject in need of such diagnosis comprising obtaining an immunoglobulin-containing biological sample from the subject, performing an assay to determine the presence or absence of one or more AD diagnostic biomarkers in the biological sample, and diagnosing AD if one or more AD diagnostic biomarkers are present.

In a preferred embodiment, the subject is a human subject. In a preferred embodiment of the invention, the immunoglobulin-containing biological sample is serum, whole blood, CSF, saliva, or sputum. A blood sample may be obtained by methods known in the art including venipuncture or a finger stick. CSF may be obtained by methods known in the art including a lumbar spinal tap. To obtain serum from blood, a sample of blood is received and centrifuged at a speed sufficient to pellet all cells and platelets, and the serum to be analyzed is drawn from the resulting supernatant. Sputum and saliva samples may be collected by methods known in the art. The biological samples may be diluted with a suitable buffer before conducting the assay. In a preferred embodiment, the biological sample is serum or whole blood.

Assays to determine the presence or absence of one or more AD diagnostic biomarkers in the biological sample are performed by contacting the sample with one or more autoantigens that are specific for an AD diagnostic biomarker under conditions that allow an immunocomplex of the autoantigen and the antibody to form, and detecting the presence of the immunocomplex

An autoantigen may comprise a protein antigen of Table 1, or a polypeptide or peptide fragment thereof containing one or more epitopes recognized by the AD diagnostic biomarker, or an epitope peptidomimetic that is recognized by the AD diagnostic biomarker. Peptidomimetics include, for example, D-peptides, peptoids, and β-peptides. The autoantigens may be purified from natural sources, or produced recombinantly or synthetically by methods known in the art, and may be in the form of fusion proteins. The autoantigens may be produced in vitro using cell-free translation systems. In one preferred embodiment, the autoantigens are produced in a mammalian or insect expression system to ensure correct folding and function. All of these methods may be automated for high throughput production.

Assays and conditions for the detection of immunocomplexes are known to those of skill in the art. Such assays include, for example, competition assays, direct reaction assays and sandwich-type assays. The assays may be quantitative or qualitative. In one preferred embodiment, the assay utilizes a solid phase or substrate to which the autoantigens are directly or indirectly attached, such as a microtiter or microassay plate, slide, magnetic bead, non-magnetic bead, column, matrix, membrane, or sheet, and may be composed of a synthetic material such as polystyrene, polyvinyl chloride, polyamide, or other synthetic polymers, natural polymers such as cellulose, derivatized natural polymers such as cellulose acetate or nitrocellulose, and glass, for example glass fibers. The substrate preferably comprises a plurality of individually addressable autoantigens immobilized on the surface. The individually addressable autoantigens are preferably immobilized on the surface to form an array. The substrates may be used in suitable shapes, such as films, sheets, or plates, or may be coated onto or bonded or laminated to appropriate inert carriers, such as paper, glass, plastic films, or fabrics. In a preferred embodiment, the substrate is a slide or a bead.

Methods for attaching the autoantigens to the support or substrate are known in the art and include covalent and noncovalent interactions. For example, diffusion of applied proteins into a porous surface such a hydrogel allows noncovalent binding of unmodified protein within hydrogel structures. Covalent coupling methods provide a stable linkage and may be applied to a range of proteins. Biological capture methods utilising a tag (e.g., hexahistidine/Ni-NTA or biotin/avidin) on the protein and a partner reagent immobilized on the surface of the substrate provide a stable linkage and bind the protein specifically and in reproducible orientation.

In one preferred embodiment, the autoantigens are coated or spotted onto the support or substrate such as chemically derivatized glass.

In one preferred embodiment the autoantigens are provided in the form of an array, and preferably a microarray. Protein microarrays are known in the art and reviewed for example by Hall et al. (2007) Mech Ageing Dev 128:161-167 and Stoevesandt et al (2009) Expert Rev Proteomics 6:145-157, the disclosures of which are incorporated herein by reference. Microarrays may be prepared by immobilizing purified autoantigens on a substrate such as a treated microscope slide using a contact spotter or a non-contact microarrayer. Microarrays may also be produced through in situ cell-free synthesis directly from corresponding DNA arrays.

Suitable methods for external production and purification of autoantigens to be spotted on arrays include expression in bacteria, as disclosed for example by Venkataram et al. (2008) Biochemistry 47:6590-6601, in yeast, as disclosed for example by Li et al. (2007) Appl Biochem Biotechnol. 142:105-124, in insect cells, as disclosed for example by Altman et al. (1999) Glycoconj J 16:109-123, and in mammalian cells, as disclosed for example by Spampinato et al. (2007) Curr Drug Targets 8:137-146.

Suitable methods for in situ (“on-chip”) protein production are disclosed, for example, by Ramachandran et al. (2006) Methods Mol. Biol 2328:1-14 and He et al. (2008) Curr. Opin Biotechnol 19:4-9.

Other methods by which proteins are simultaneously expressed and immobilized in parallel on an array surface are also known in the art and may be used in accordance with the present invention. For example, in the Protein In Situ Arrays (PISA) method (He et al. (2001) Nucleic Acids Res 29:e73), proteins are made directly from DNA, either in solution or immobilized, and become attached to the array surface as they are made through recognition of a tag sequence. The proteins are expressed in parallel in vitro utilizing a cell free system, commonly rabbit reticulocyte or E. coli S30, to perform coupled transcription and translation. In this method, protein expression is performed on a surface which is precoated with an immobilizing agent capable of binding to the tag. Thus after each protein is translated, it becomes fixed simultaneously and specifically to the adjacent surface, while the other materials can subsequently be washed away. Microarrays are produced directly onto glass slides, either by mixing the DNA with the cell free lysate system before spotting or by a multiple spotting technique (MIST) in which DNA is spotted first followed by the expression system.

In the system known as Nucleic Acid Programmable Protein Array (NAPPA) (Ramachandran et al. (2004) Science 305:86-90), transcription and translation from an immobilized (as opposed to a solution) DNA template allow conversion of DNA arrays to protein arrays. In this method, biotinylated cDNA plasmids encoding the proteins as GST fusions are printed onto an avidin-coated slide, together with an anti-GST antibody acting as the capture entity. The cDNA array is then covered with rabbit reticulocyte lysate to express the proteins, which become trapped by the antibody adjacent to each DNA spot, the proteins thereby becoming immobilized with the same layout as the cDNA. This technology generates a protein array in which the immobilized proteins are present together with DNA and a capture agent.

Another suitable method for generating a protein array is the DNA Array to Protein Array (DAPA) method. This method for in situ protein arraying uses an immobilized DNA array as the template to generate ‘pure’ protein arrays on a separate surface from the DNA, and also can produce multiple copies of a protein array from the same DNA template (He et al. (2008) Nature Methods, 5:175-7). Cell-free protein synthesis is performed in a membrane held between two surfaces (e.g., glass slides), one of which is arrayed with DNA molecules while the other surface carries a specific reagent to capture the translated proteins. Individual, tagged proteins are synthesized in parallel from the arrayed DNA, diffuse across the gap and are subsequently immobilized through interaction with the tag-capturing reagent on the opposite surface to form a protein array. Discrete spots which accurately reflect the DNA in position and quantity are produced. Replicate copies of the protein array can be obtained by reuse of the DNA.

Array fabrication methods include robotic contact printing, ink-jetting, piezoelectric spotting and photolithography. For example, purified autoantigens of the invention that are produced and purified externally may be spotted onto a microarray substrate using a flexible protein microarray inkjet printing system (e.g., ArrayJet, Roslin, Scotland, UK) to provide high quality protein microarray production. The precise rows and columns of autoantigens may be converted to detectable spots denoting both the presence and amount of serum diagnostic biomarkers that have been bound.

The production of the microarrays is preferably performed with commercially available printing buffers designed to maintain the three-dimensional shape of the autoantigens. In one preferred embodiment, the substrate for the microarray is a nitrocellulose-coated glass slide.

The assays are performed by methods known in the art in which the one or more autoantigens are contacted with the biological sample under conditions that allow the formation of an immunocomplex of an autoantigen and an antibody, and detecting the immunocomplex. The presence and amount of the immunocomplex may be detected by methods known in the art, including label-based and label-free detection. For example, label-based detection methods include addition of a secondary antibody that is coupled to an indicator reagent comprising a signal generating compound. The secondary antibody may be an anti-human IgG antibody. Indicator reagents include chromogenic agents, catalysts such as enzyme conjugates, fluorescent compounds such as fluorescein and rhodamine, chemiluminescent compounds such as dioxetanes, acridiniums, phenanthridiniums, ruthenium, and luminol, radioactive elements, direct visual labels, as well as cofactors, inhibitors and magnetic particles. Examples of enzyme conjugates include alkaline phosphatase, horseradish peroxidase and beta-galactosidase. Methods of label-free detection include surface plasmon resonance, carbon nanotubes and nanowires, and interferometry. Label-based and label-free detection methods are known in the art and disclosed, for example, by Hall et al. (2007) and by Ray et al. (2010) Proteomics 10:731-748. Detection may be accomplished by scanning methods known in the art and appropriate for the label used, and associated analytical software.

In one preferred embodiment of the present invention, fluorescence labeling and detection methods are used to detect the immunocomplexes. Commericially available slide scanners (e.g. the Genepix 4000B slide scanner (Molecular Devices, Inc.) with associated analytical software may be used. In one preferred embodiment, the immunocomplex is probed with fluorescent-labeled (e.g., Alexa-Fluor (Invitrogen)) anti-human antibody and the intensity of fluorescence at each protein spot is measured using a microarray scanner. Commercially available software (e.g. GenePix Pro 5.0 software (Axon instruments)) may be used to extract the net median pixel intensities for individual features from the digital images produced by the scanner. Data may be normalized by comparing median values of multiple identical control spots in different regions of the same array.

Detection of diagnostic immunocomplexes is indicative of the presence of AD diagnostic biomarkers in the biological sample, and thus a positive diagnosis of AD.

In another embodiment, the present invention provides a method of generating a patient-specific AD diagnostic biomarker profile comprising obtaining a serum-containing biological sample from a patient, performing an assay to determine the presence or absence of AD diagnostic biomarkers in the biological sample, and generating a patient-specific AD diagnostic biomarker profile of the AD diagnostic biomarkers present in the sample. The assay is performed as described hereinabove.

The results of the assay provide an AD diagnostic biomarker profile for the patient that is useful to diagnose AD and optimize a treatment regimen for AD.

In another embodiment, the present invention provides a method of identifying a subject at risk for developing AD comprising obtaining an immunoglobulin-containing biological sample from the subject, performing an assay to determine the presence or absence of one or more AD diagnostic biomarkers in the biological sample, and identifying the subject as at risk for developing AD if one or more of the AD diagnostic biomarkers is present. The assay is performed as described herein above.

In yet another embodiment, the present invention provides a substrate on which one or more autoantigens that are specific for an AD diagnostic biomarker are immobilized. The present invention also provides, in another embodiment, a microarray comprising a substrate on which one or more autoantigens that are specifically bound by an AD diagnostic biomarker are immobilized. The substrates and microarrays may be made as described hereinabove and are useful for creating AD diagnostic biomarker profiles and for the diagnosis of AD. An autoantigen may comprise a protein antigen of Table 1, or a polypeptide or peptide fragment thereof containing one or more epitopes recognized by the AD diagnostic biomarker, or an epitope peptidomimetic that is recognized by the AD diagnostic biomarker. Peptidomimetics include, for example, D-peptides, peptoids, and β-peptides. The substrate and microarrays may contain, as the autoantigen, at least one of the protein antigens of Table 1 or fragments thereof containing one or more epitopes recognized by the AD diagnostic biomarker.

In another embodiment, the substrate and microarrays may contain, as the autoantigen, at least one of the protein antigens of Table 2, or or a polypeptide or peptide fragment thereof containing one or more epitopes recognized by the AD diagnostic biomarker, or an epitope peptidomimetic that is recognized by the AD diagnostic biomarker. Peptidomimetics include, for example, D-peptides, peptoids, and β-peptides. The protein antigens in Tables 2-5 are identified by art-accepted names as well as database identification numbers. The database identification numbers refer to the publically available protein databases of the National Center for Biotechnology Information (NCBI) which are well-known and accessible to those of ordinary skill in the art.

TABLE 2 Database ID Description BC030984.1 cDNA clone MGC: 32654 IMAGE: 4701898, complete cds PHR5001 Recombinant human CTLA-4/Fc BC016380.1 cDNA clone MGC: 27376 IMAGE: 4688477, complete cds BC015833.1 cDNA clone MGC: 27152 IMAGE: 4691630, complete cds BC099907.1 General transcription factor II-I BC051695.1 FERM domain containing 8 (FRMD8) BC040106.1 hypothetical protein HSPC111 (HSPC111) NM_003141.2 tripartite motif-containing 21 (TRIM21) NM_003384.1 vaccinia related kinase 1 (VRK1) BC004236.2 ubiquitin-conjugating enzyme E2S (UBE2S) BC001662.1 MAP kinase-activated protein kinase 3 NM_017588.1 WD repeat domain 5 (WDR5), transcript variant 1 NM_032377.2 elongation factor 1 homolog (S. cerevisiae) (ELOF1) NM_021032.2 fibroblast growth factor 12 (FGF12), transcript variant 1 NM_000984.2 ribosomal protein L23a (RPL23A) BC064984.1 additional sex combs like 1 (Drosophila) (ASXL1) NM_012387.1 peptidyl arginine deiminase, type IV (PADI4) NM_001641.2 APEX nuclease (multifunctional DNA repair enzyme) 1 (APEX1), transcript variant 1 NM_001896.2 casein kinase 2, alpha prime polypeptide (CSNK2A2) NM_014481.2 APEX nuclease (apurinic/apyrimidinic endonuclease) 2 (APEX2), nuclear gene encoding mitochondrial protein NM_014280.1 DnaJ homolog subfamily C member 8 BC007228.1 CSAG family, member 3A (CSAG3A) BC021174.1 Small EDRK-rich factor 1 BC033758.1 centaurin, alpha 2 (CENTA2) BC005248.1 eukaryotic translation initiation factor 1A, Y-linked (EIF1AY) BC022098.1 cDNA clone MGC: 31944 IMAGE: 4878869, complete cds NM_024754.2 pentatricopeptide repeat domain 2 (PTCD2) NM_024316.1 leukocyte receptor cluster (LRC) member 1 (LENG1) NM_015920.3 40S ribosomal protein S27-like protein BC048970.1 tubulin tyrosine ligase-like family, member 7 (TTLL7) NM_003668.2 mitogen-activated protein kinase-activated protein kinase 5 (MAPKAPK5), transcript variant 1 NM_007278.1 GABA(A) receptor-associated protein (GABARAP) NM_006838.1 methionyl aminopeptidase 2 (METAP2) NM_018439.1 Impact homolog (mouse) (IMPACT) NM_002013.2 FK506 binding protein 3, 25 kDa (FKBP3) NM_018956.2 chromosome 9 open reading frame 9 (C9orf9) NM_004987.3 LIM and senescent cell antigen-like-containing domain protein 1 BC004292.1 PHD finger protein 15 (PHF15) NM_133494.1 NIMA (never in mitosis gene a)-related kinase 7 (NEK7) NM_145063.1 chromosome 6 open reading frame 130 (C6orf130) NM_021104.1 ribosomal protein L41 (RPL41), transcript variant 1 NM_006223.1 protein (peptidylprolyl cis/trans isomerase) NIMA-interacting, 4 (parvulin) (PIN4) NM_003135.1 Signal recognition particle 19 kDa protein NM_015933.1 coiled-coil domain containing 72 (CCDC72) NM_001031.4 40S ribosomal protein S28 BC022524.1 fibroblast growth factor 12 (FGF12) NM_001028.2 ribosomal protein S25 (RPS25) NM_001997.2 Finkel-Biskis-Reilly murine sarcoma virus (FBR-MuSV) ubiquitously expressed (FAU) NM_080659.1 chromosome 11 open reading frame 52 (C11orf52)

In another embodiment, the substrate and microarrays may contain, as the autoantigen, at least one of the protein antigens of Table 3, or a polypeptide or peptide fragment thereof containing one or more epitopes recognized by the AD diagnostic biomarker, or an epitope peptidomimetic that is recognized by the AD diagnostic biomarker. Peptidomimetics include, for example, D-peptides, peptoids, and β-peptides.

TABLE 3 Database ID Description BC051695.1 FERM domain-containing protein 8 (FRMD8) NM_024754.2 Pentatricopeptide repeat-containing protein 2 (PTCD2) NM_021104.1 60S ribosomal protein L41(RPL41) NM_032855.1 Hematopoietic SH2 domain-containing protein (HSH2D)

In another embodiment of one aspect of the present invention, the microarray contains autoantigens consisting of FERM domain-containing protein 8 (FRMD8), 60S ribosomal protein L41(RPL41), pentatricopeptide repeat-containing protein 2 (PTCD2), and hematopoietic SH2 domain-containing protein (HSH2D) or fragments thereof containing one or more epitopes recognized by an AD diagnostic biomarker, or epitope peptidomimetics that are recognized by the AD diagnostic biomarker. Peptidomimetics include, for example, D-peptides, peptoids, and β-peptides. In another embodiment, the microarray contains autoantigens consisting of FERM domain-containing protein 8 (FRMD8) and hematopoietic SH2 domain-containing protein (HSH2D) or fragments thereof containing one or more epitopes recognized by an AD diagnostic biomarker.

In one preferred embodiment of the present invention, the substrate and microarrays may contain, as the autoantigen, at least one of the protein antigens of Table 4, or a fragment thereof containing one or more epitopes recognized by an AD diagnostic biomarker, or an epitope peptidomimetic that is recognized by the AD diagnostic biomarker. Peptidomimetics include, for example, D-peptides, peptoids, and β-peptides. In another preferred embodiment of the present invention, the substrate and microarrays contain all of the protein antigens of Table 4.

TABLE 4 Database ID Description BC051695.1 FERM domain containing 8 (FRMD8) NM_015833.1 adenosine deaminase, RNA-specific, B1 (RED1 homolog rat) (ADARB1), transcript variant 2 NM_002305.2 lectin, galactoside-binding, soluble, 1 (galectin 1) (LGALS1) NM_001641.2 APEX nuclease (multifunctional DNA repair enzyme) 1 (APEX1), transcript variant 1 NM_024316.1 leukocyte receptor cluster (LRC) member 1 (LENG1) NM_014280.1 DnaJ homolog subfamily C member 8 PHC1244 chemokine (C-C motif) ligand 19 (CCL19) BC064984.1 additional sex combs like 1 (Drosophila) (ASXL1) NM_021104.1 ribosomal protein L41 (RPL41), transcript variant 1 BC004236.2 ubiquitin-conjugating enzyme E2S (UBE2S) NM_012387.1 peptidyl arginine deiminase, type IV (PADI4) NM_003384.1 vaccinia related kinase 1 (VRK1) NM_004113.3 fibroblast growth factor 12 (FGF12), transcript variant 2 BC021174.1 Small EDRK-rich factor 1 NM_001001794.1 family with sequence similarity 116, member B (FAM116B) NM_032377.2 elongation factor 1 homolog (S. cerevisiae) (ELOF1) NM_024754.2 pentatricopeptide repeat domain 2 (PTCD2) NM_000984.2 ribosomal protein L23a (RPL23A) NM_139016.2 chromosome 20 open reading frame 198 (C20orf198) NM_024668.1 ankyrin repeat and KH domain containing 1 (ANKHD1), transcript variant 3

In another embodiment of the present invention, the microarrays also contain autoantigens that are reactive with biomarkers diagnostic for Parkinson's Disease (PD) but not for AD, and thus permit differentiation of AD from PD. Autoantigens diagnostic for PD but not AD include, for example, the proteins of Table 5, and fragments thereof containing one or more epitopes recognized by a PD diagnostic biomarker and epitope peptidomimetics that are recognized by the PD diagnostic biomarker. Peptidomimetics include, for example, D-peptides, peptoids, and β-peptides.

TABLE 5 Database ID Description NM_003177.3 Spleen tyrosine kinase (SYK) BC_019015.2 Mediator of RNA polymerase II transcription subunit 29 (MED29) BC003551 Protein-glutamine gamma-glutamyltransferase 2 (TGM2) PV3851 MAP/microtubule affinity-regulating kinase-4 (MAPrk4) BC001755.1 Leiomodin-1

In a further embodiment, the present invention provides a kit for detecting AD-specific antibodies in a sample. A kit comprises one or more autoantigens that are specific for an AD diagnostic biomarker and means for determining binding of the autoantigen to an AD diagnostic biomarker in the sample. The kit may also comprise packaging material comprising a label that indicates that the one or more autoantigens of the kit can be used for the identification of AD. Other components such as buffers, controls, detection reagents, and the like known to those of ordinary skill in art may be included in such the kits. The kits are useful for detecting AD diagnostic biomarkers and for diagnosing AD.

The following examples serve to further illustrate the present invention.

EXAMPLE 1

Materials and methods

Animals

Swiss-Webster mice were obtained from Taconic Farms (Hudson, N.Y.) and used for experiments at 3-6 months of age. Sprague-Dawley rats were also obtained from Taconic Farms and used at 7-9 weeks of age. Both were maintained on ad libitum food and water with 12-hour light/dark cycle in an AALAC-accredited vivarium. Animals use was reviewed and approved by the UMDNJ IACUC.

Human Brain Tissue

Brain tissue from patients with sporadic AD (n=23, age range=71-88) and age-matched, neurologically normal individuals (n=14, age range=69-83) were obtained from the Harvard Brain Tissue Resource Center (Belmont, Mass.), the Cooperative Human Tissue Network (Philadelphia, Pa.), the UCLA Tissue Resource Center (Los Angeles, Calif.) and Slidomics (Cherry Hill, N.J.). Post-mortem intervals were <24 h and pathological confirmation of AD was evaluated according to criteria defined by the National Institute on Aging and the Reagan Institute Working Group on Diagnostic Criteria for the Neuropathological Assessment of AD (Hyman and Trojanowski (1997) J Neuropathol Exp Neural. 56, 1095-7). Formalin-fixed tissues were processed for routine paraffin embedding and sectioning according to established protocols. Control tissues exhibited minimal localized microscopic AD-like neuropathology.

Antibodies

Aβ42 antibodies were obtained from Millipore International (Temecula, Calif.) (polyclonal, Cat. No. AB5078P, dilution=1:50) and Pharmingen (San Diego, Calif.) (polyclonal Cat. No. 4767, dilution=1:50). Biotinylated anti-human IgG antibodies for immunohistochemistry were obtained from Vector Laboratories (Burlingame, Calif.) (host: goat, Cat. No. PK-6103, dilution=1:100). Peroxidase-conjugated anti-human IgG antibodies for western blotting were obtained from Thermo Scientific (Rockford, Ill.) (host: goat, Cat. No. 31410, dilution=1:200,000). The following antibodies were used for treatments of mouse organotypic brain slice cultures: anti-alpha7 nicotinic acetylcholine receptor (C-20, Santa Cruz Biotechnology, Santa Cruz, Calif.); anti-GluR2 (polyclonal N19, Santa Cruz Biotechnology, Santa Cruz, Calif.); anti-beta tubulin (D-10, Santa Cruz Biotechnology, Santa Cruz, Calif.). The specificity of these antibodies was confirmed by western blotting.

Human Sera

Human serum samples [AD (n=52, age range=61-97 years); age-matched controls (n=28, age range=51-86); and younger healthy controls (n=28, age range=19-30 years)] were obtained from Analytical Biological Services Inc (Wilmington, Del.). Samples were numerically coded and included the following information: age and sex of the patient, the presence or absence of a detectable neurological disease and, if present, an indication of disease severity and estimated post-mortem interval. Use of these samples was approved by the UMDNJ IRB.

Immunohistochemistry

Immunohistochemistry was carried out using paraffin-embedded brain tissues as previously described (D'Andrea et al. (2001) Histopathology 38, 120-34; Nagele et al. (2002) Neuroscience 110, 199-211). Briefly, tissues were deparaffinized using xylene and rehydrated through a graded series of decreasing concentrations of ethanol. Antigenicity was enhanced by microwaving sections in citrate buffer. Endogenous peroxidase was quenched by treating sections with 0.3% H₂O₂ for 30 min. Sections were incubated in blocking serum and then treated with primary antibodies at appropriate dilutions for 1 hr at room temperature. After a thorough rinse in PBS, biotin-labeled secondary antibody was applied for 30 min. Sections were treated with the avidin-peroxidase complex (Vectastain ABC Elite, Vector Laboratories, Inc., Foster City, Calif.) and visualized with 3-3-diaminobenzidine-4-HCL (DAB)/H₂O₂ (Imm-Pact-DAB) (Vector). Sections were then lightly counterstained with hematoxylin, dehydrated through increasing concentrations of ethanol, cleared in xylene and mounted in Permount. Controls consisted of brain sections treated with non-immune serum or omission of the primary antibody. Specimens were examined and photographed with a Nikon FXA microscope, and digital images were recorded using a Nikon DXM1200F digital camera and processed and analyzed using Image Pro Plus (Phase 3 Imaging, Glen Mills, Pa.) and Cell Profiler image analysis softwares.

Preparation of Adult Rat Brain Proteins

To prepare rat brain protein fractions, fresh rat brain tissue was removed from storage at −80° C. and placed in a 1 mM phenylmethylsulfonyl fluoride, 50.0 mM Tris-HCL buffer solution, pH 7.4, at a 10.0 ml/g ratio along with protease inhibitor cocktail (Sigma-Aldrich, St. Louis, Mo.) at a 0.5 ml/g ratio. Using a pre-cooled Dounce homogenizer (Arrow Engineering Co., Inc., Hillside, N.J.) at a setting of four, brain samples were subjected to homogenization. Brain samples were then centrifuged at 3,000 rpm using a Beckman CS-6R centrifuge (Beckman Coulter Inc, Brea, Calif.) equipped with a swing-rotor at 4° C. for a period of 10 min to remove intact cells and large debris. The supernatant was retained as whole brain protein fraction. Protein concentrations were determined using the Bradford Assay.

Detection of Autoantibody Targets Via Western Blotting

Western blot analysis was performed to determine the brain membrane targets of serum auto-antibodies. First, 12.5% SDS-polyacrylamide separating gels were cast using the Mini PROTEAN 3 System (165-3302, BioRad, Hercules, Calif.) and overlain with stacking gels (4.0%). 100.0 μg of protein sample was added to sample buffer and applied to the gel alongside PageRuler™ Prestained Protein Ladder Plus (SM1811, Fermentas, Glen Burnie, Md.). Proteins were then fractionated at 130V for 7 minutes, followed by 100V for the remainder of the resolving time. Proteins were then transferred to Hybond-ECL Nitrocellulose Membrane (RPN3032D, Amersham, Piscataway, N.J.) for 75 minutes at 180 mA. Blots were blocked in 5.0% non-fat dried milk dissolved in PBS-Tween (PBS-T) then transferred to human serum samples (primary antibody), diluted 1:500 in blocking solution, for overnight incubation at 4° C. The following morning, blots were thoroughly rinsed in PBS-T then placed in the appropriately diluted peroxidase-conjugated secondary antibody and incubated for one hour at 4° C. Blots were then thoroughly rinsed in PBS-T then quickly rinsed in dH₂O to remove phosphate buffer. Blots were then developed using the Pierce enhanced chemiluminescence (ECL) substrate (32106, Pierce, Rockford, Ill.) and autoradiography film (XAR ALF 1824, Lab Scientific, Livingston, N.J.). Each western blot for a given serum sample was performed in triplicate.

Mouse organotypic Brain Slice Cultures and Treatments

Organotypic adult mouse brain slice cultures (MBOCs) were prepared using the technique of Stoppini et al. (1991) J Neurosci Methods. 37, 173-82. Neurons in these cultures have been shown to accumulate exogenous Aβ42 (detectable within 4 h of exposure to 100 nM Aβ42) (Bahr et al., (1998) J Comp Neurol. 397, 139-47 ; Harris-White et al., (1998) J Neurosci. 18, 10366-74; Malouf, (1992) Neurobiol Aging. 13, 543-51 ; Stoppini et al. (1991)). Brains from Swiss-Webster mice (3-6 months old) were isolated under sterile conditions and transverse coronal slices (0.5-0.75 mm thick) through desired brain regions were prepared using a McIlwain tissue chopper, placed on 30 mm Millicell-CM culture inserts (Millicell-CM, Millipore, Bedford, Mass., USA), and allowed to stabilize in serum-free medium (DMEM) briefly (one hour) or in 25% inactivated horse serum, 25% Hanks' BSS, 50% DMEM, 25 mg/l penicillin-streptomycin) overnight prior to treatment. Following stabilization, cultures were exposed to serum-free medium (DMEM alone) or complete medium (25% inactivated horse serum, 25% Hanks' BSS, 50% DMEM, 25 mg/l penicillin-streptomycin) containing Aβ42 peptide (100 nM), anti-GluR2 antibody (diluted 1:250), human serum samples (diluted 1:50), anti-α7nAChR antibody (diluted 1:1000), anti-β-tubulin antibody (diluted 1:200). Control slices received medium only. MBOCs were treated for up to 72 h at 37° C. in a 5% CO₂-enriched atmosphere. Aβ42 was solubilized to the monomeric form using the method of (Zagorski et al. (1999) Methods Enzymol. 309, 189-204).

Image Analysis

The extent of Aβ42 accumulation in MBOCs treated with 100 nM Aβ42 with or without human serum or antibodies directed against the α7nAChR or GluR2 was determined using quantitative immunohistochemistry. MBOCs treated as described above were first immunostained with anti-Aβ42 antibodies under identical conditions. Images were then recorded under identical illumination and camera settings using a Nikon FXA microscope equipped with a Nikon CCD camera and image analysis softwares (Image Pro Plus and Cell Profiler). Relative amounts of intracellular Aβ42-positive deposit per Aβ42-positive cell were determined and compared among the different treatment groups. The significance of differences in the amount of intracellular Aβ42 within cells were determined by the Student's t-test. Controls for immunohistochemistry included nonimmune serum or detection antibody only.

EXAMPLE 2 Brain Reactive Autoantibodies in Human Sera

Sera from AD patients (n=52, age range 61-97 years), age-matched, non-demented control subjects (n=28, age range 51-86 years) and younger healthy individuals (n=28, age range 19-30 years) were tested for the presence of brain-reactive autoantibodies. For western analyses, individual sera were tested for the presence of brain-reactive autoantibodies by probing proteins obtained from whole cell homogenate derived from adult rat brain. Results confirmed the presence of brain-reactive autoantibodies in all sera from the three groups tested. The number of immunoreactive protein bands generated by each serum sample was similar for all three subject groups: mean=5.1+/−3.1 for AD sera (n=52); 7.4+/−4.0 for age-matched control sera (n=28); and 6.0+/−3.8 for younger healthy control sera (n=28). Comparable results were obtained when human sera were used to probe mouse and human brain proteins. Based on apparent molecular weights in western blots, a few potentially common protein bands were noted within and among the three subject groups.

EXAMPLE 3 IgG-Positive Neurons in Brain Regions Exhibiting AD Pathology

Ig-positive neurons in postmortem AD brains have been reported (Bouras et al. (2005) Brain Res Brain Res Rev. 48, 477-87; Clifford et al. (2007) Brain Res. 1142, 223-36; Deane and Zlokovic (2007) Curr Alzheimer Res. 4, 191-7; Franceschi et al. (1989) J Gerontol. 44, M128-30; Kalaria (1999) Ann NY Acad Sci. 893, 113-125; Kulmala et al. (1987) Exp Aging Res 13:67-72; Loeffler et al. (1997) Neurochem Res. 22, 209-14; Mooradian (1988) Neurobiol Aging. 9, 31-9; Nandy et al. (1975) J Gerontol. 30, 269-74; Stein et al. (2002) J Neuropathol Exp Neurol. 61, 1100-8). In this example, immunohistochemistry using anti-human IgG antibodies was employed to test for the presence of IgG-immunopositive brain components in 23 AD and 14 age-matched control brains. IgG-positive neurons with immunolabeled cell bodies and dendrite trunks were found in all brains that were examined . IgG-positive neurons were far more abundant, widespread and intensely immunostained in AD brains than in corresponding age-matched control brains. In the latter, IgG-positive neurons were most often encountered as scattered individual cells and small cell clusters separated by relatively large expanses of brain tissue that were completely devoid of IgG-positive cells. In AD brains, IgG-positive neurons were particularly abundant in brain regions known to be vulnerable to AD-associated pathological changes (e.g., temporal cortex, entorhinal cortex and hippocampus). In both AD and control brains, IgG immunoreactivity was consistently and preferentially associated with pyramidal neurons, and these cells often showed marked individual variations in the intensity of IgG immunolabeling, sometimes with IgG-positive and -negative neurons present in close proximity. Similar variations in neuronal IgG immunostaining intensity were noted in neurons of the hippocampus. In pyramidal neurons, IgG immunoreactivity was most conspicuous in the cell body and proximal segment of the main dendrite trunk. Most of the smaller neurons, astrocytes and microglia that were interspersed among pyramidal cells were IgG-negative. In three of the 23 AD brains examined, both astrocytes and pyramidal neurons were IgG-positive, but this was not observed in age-matched control brains.

EXAMPLE 4 Relationship Between IgG Immunoreactivity and Aβ42 Deposition

Sections of post-mortem AD brain tissue were probed with antibodies specific for human IgG and Aβ42. In regions of the cerebral cortex and hippocampus showing mild AD pathology (i.e., regions with sequestered intraneuronal A(342 deposits but few amyloid plaques), Aβ42-immunopositive neurons also exhibited intense IgG immunostaining. Two sets of consecutive sections were immunostained to reveal the relative distribution of Aβ42 and IgG in the cerebral cortex of AD brains. In regions exhibiting mild AD pathology, both IgG and Aβ42 were colocalized to the same neurons appearing in both sections. Likewise, in cortical regions showing more advanced pathology (as judged by the increased deposition of Aβ42 within neurons and amyloid plaques), the amount of interstitial and intraneuronal IgG was substantially increased. In addition to the typical large juxtanuclear deposits of Aβ42-rich material in pyramidal neurons, the main dendrite trunks of these cells frequently contained abundant small Aβ42-positive granules of uniform size. These results demonstrate the temporal and spatial coincidence of intraneuronal Aβ42 deposition and IgG immunolabeling within pyramidal neurons.

EXAMPLE 5

Reactivity of Human Serum Antibodies with Living Neurons

To test for the reactivity (i.e., binding) of human serum antibodies with the surfaces of living neurons, adult mouse brain organotypic (brain slice) cultures (MBOCs) were maintained in medium with or without diluted human serum for up to 72 h. MBOCs retain the adult brain histological architecture for up to several weeks under proper conditions and have been shown to contain neurons that internalize and accumulate exogenous, soluble Aβ42 peptide (Bahr et al. (1998) ; Harris-White et al. (1998); Malouf (1992); Stoppini et al. (1991). The binding of human IgG to neurons in MBOCs was detected by immunohistochemistry using anti-human IgG antibodies. Addition of human serum to the culture medium resulted in intense and selective IgG immunolabeling of living adult mouse neurons, whereas controls not treated with serum showed no inherent IgG immunoreactivity. The pattern of background IgG immunostaining in human serum-treated MBOCs suggests that dendrites and/or synaptic connections may also be IgG-positive. As was shown in postmortem human AD brains described above, pyramidal neurons of the cerebral cortex of MBOCs were consistently the most intensely immunopositive cells.

EXAMPLE 6 Effect of Autoantibodies on Internalization of Exogenous Aβ42

This example utilizes the property of cross-reactivity of the antibodies in human serum with rodent brain proteins as demonstrated above in western blots and in brain tissue as shown above in immunohistochemical preparations. MBOCs were treated with 100 nM Aβ42 in the presence or absence of individual human serum samples diluted 1:50 in otherwise serum-free medium for 1, 3, 24, 48 and 72 h and the relative amounts of intraneuronal Aβ42 were quantified using image analysis for MBOCs treated for 24 h. MBOCs treated with 100 nM Aβ42 alone for 24 h showed no human IgG immunostaining and only minimal Aβ42 immunoreactivity. On the other hand, when MBOCs were exposed to human serum autoantibodies and Aβ42 peptide for 24 h, pyramidal neurons selectively showed a dramatic increase in intracellular Aβ42 accumulation over that of controls treated with Aβ42 peptide or serum alone for the same time period. Within these neurons, Aβ42-positive material was localized to dense cytoplasmic granules that were concentrated in the neuronal perikaryon and proximal dendrite trunk. Measurements of the relative amounts of intraneuronal Aβ42 in MBOCs using image analysis after 24 h of treatment revealed that the addition of human serum to medium containing 100 nM Aβ42 caused a many-fold increase in neuronal Aβ42 immunoreactivity over that in cells treated with Aβ42 alone. Morphological evidence of significant cell death and loss of Aβ42-burdened neurons in MBOCs was not observed

EXAMPLE 7 Effect of Purified Antibodies Targeting Neural Surface Proteins on Internalization of Exogenous Aβ42

MBOCs were treated for 24 h with commercially available antibodies directed against two neuronal receptors that are known to be abundantly expressed on neuronal cell surfaces, the alpha7 nicotinic acetylcholine receptor (α7nAChR) and the glutamate R2 (GluR2) receptor. Both antibodies were found to be effective in increasing intraneuronal Aβ42 accumulation, again selectively in pyramidal neurons and well above levels seen in cultures treated with Aβ42 alone . To explore whether neuronal cell surface reactivity of IgG is required for enhancement of exogenous Aβ42 internalization, MBOCs were also treated with an antibody directed against the common intracellular protein, beta-tubulin, along with 100 nM Aβ42. Treatment with beta-tubulin antibody resulted in levels of neuronal Aβ42 accumulation that were comparable to treatment with 100 nM Aβ42 alone.

EXAMPLE 8 Identification of Biomarkers Diagnostic for AD Western Analysis

As disclosed hereinabove, biochemical confirmation of the presence of brain-reactive autoantibodies in individual human sera was carried out using western analysis. In addition, total rat brain protein, which is immunoreactive to human autoantibodies as shown hereinabove, was used to compare sera from patients with AD, age-matched neurologically normal controls and younger healthy individuals. Based on estimated molecular weights alone, the resulting distributions of molecular weights for individual target proteins were analyzed using the pattern recognition computer program called A.I. Solver (Silversoft Solutions).

Based on the recognition of specific patterns of distribution of molecular weights of autoantibody target proteins, A.I. Solver was able to distinguish western blots derived from AD patient's sera from that of age-matched controls and younger healthy subjects 98% of the time. This example demonstrates the existence of AD-specific protein antibodies in the blood that bind to brain protein target antigens. Next, a protein microarray platform was used identify the specific subset of autoantibodies and their target proteins that are useful to effectively diagnose AD.

Micrarray Procedure

The protein microarray platform used to identify diagnostic antibodies and prove the efficacy of a protein microarray diagnostic was Invitrogen's ProtoArray® Human Protein Microarray v5.0. It is a high-density protein microarray containing thousands of purified human proteins for protein interaction screening. Each human open reading frame (ORF) is expressed as an N-terminal GST fusion protein using a baculovirus expression system, purified from insect cells, and printed in duplicate on a nitrocellulose-coated glass slide. The Immune Response Biomarker Profiling application was used as it is best suited the needs of a diagnostic. All reagents and materials were purchased directly through Invitrogen. The recommended Invitrogen ProtoArray® protocol was strictly adhered to at all times and is incorporated herein by reference in its entirety. The array was probed with diluted (1:500) human serum or plasma.

Microarray Scanning

The protein microarrays were scanned using the recommended Axon Genepix 4000b imager. Individual slides were inserted into the imager and then scanned using 100% laser power, 635 nm excitation wavelength, PMT 600, and Sum pixel size. Data was extracted from the image by syncing it with a Genepix Array List (.GAL) file obtained from Invitrogen. GAL files describe the location and identity of all spots on the protein microarray and are used by Genepix Pro software (by Molecular Devices) to generate files that contain pixel intensity information for all features on the array. Genepix Pro then creates a .GPR (Genepix Pixel Results) file that lists all of the pixel intensity data for each protein spot on the microarray in text-only spreadsheet format. It is the GPR file that is imported into Prospector for data analysis.

Normalization

After acquiring the individual microarray data by scanning the microarrays with an Axon Genepix 4000b imager and performing the initial quantification with Genepix Pro software, the resulting data were normalized so as to allow microarray-to-microarray comparison. For this, Invitrogen's proprietary software, Prospector; more specifically, the Immune Response Biomarker Profiling Toolbox application, was used. Each microarray's gpr file was imported into the program, analyzed, and normalized to a linear model.

Fitting the data to a linear model was performed through a robust regression by means of an iteratively re-weighted least-square procedure with an M-estimator, like the median. The linear model uses log-transformed signals to estimate and correct the variations. For each spot replicate r(=1,2) of protein feature k(=1, . . . , n_(f)) in sub-array j(=1, . . . , 48) on slide i(=1, . . . , n_(s),) the following model was fit:

y _(ijkr)=α_(i)+β_(j)+τ_(k)+ε_(ijkr)

where y_(ijkr) is the observed signal in log 2 scale, a is the slide effect, β_(j) is the sub-array/block effect (including printing pin effect), τ_(k) is the “true” signal of the protein feature (different protein content printed in different concentration), and ε_(ijkr) is the error, assuming ε_(ijkr)˜N(0,σ²). After the coefficients of these effects were estimated using control proteins, the normalized signal in its original scale for each spot was calculated as:

S _(ijkr)2̂(y _(ijkr)−α_(i)−β_(j))

After normalization, the microarray data was fully adjusted for error and individual variation; formal analysis was begun. It was this adjusted data from which diagnostic significance was determined.

Data Analysis

There are multiple accepted methods of determining the diagnostic significance of microarray fluorescence data. To ensure the reproducibility and accuracy of our results, data were analyzed three separate times using three independent and distinct methods. The methods chosen are among the most reliable and consistent available, and are commonly used in similar studies. The methods are: M-Statistical Prevalence, Nearest Shrunken Centroid Analysis, and Random Forest Decision-Making Trees. To harness each of these unbiased statistical quantification schemes, Prospector, PAM, and R's Random Forest, respectively, were utilized. Each of these programs evaluated the protein microarray data to determine which proteins were most significant to diagnose Alzheimer's Disease. The lists reflected one another almost exactly, thus demonstrating that protein microarrays are useful as a successful diagnostic. The statistical methods, programs involved, and results generated are described below.

M-Statistical Analysis

As well as interpreting and normalizing the raw fluorescence data generated by Genepix Pro, Prospector was used to generate M-Statistics that were, in turn, used to evaluate each protein's diagnostic significance. Briefly, M-statistics were used to determine the number of assays in one group (e.g. Alzheimer's or Control) that have a signal value for a protein greater than the highest observed signal value of this probe in the comparison group. The M order statistic for the group n_(y) of size ny compared to group x of size n_(x) is given by the formula:

M ^(y) _(i,above,between)=Σ1_({yk>x(i)+between})1_({yk>above})

where x_((i)) is the i_(th) largest value of the group x, and above and between are the calculation parameters. A p-value was calculated as the probability of having M value greater or equal than M_(i). Prospector selected the M statistic with the lowest p-value and reported this M_(max) value and order, as well as a corresponding p-value and protein prevalence estimate. The values were viewed as a spreadsheet in Microsoft Excel Workbook format, and filtered to provide a list of the most effective indicators of group differences, i.e., the proteins that are the best diagnostic markers.

PAM (Prediction Analysis of Microarrays)

Another method of interpreting protein microarray results and yielding protein significance is PAM, or Prediction Analysis of Microarrays. PAM is a statistical technique for class prediction that uses nearest shrunken centroids. It is run as a Microsoft Excel Macro and has been used extensively in characterizing microarray results (Tibshirani et al. (2002) Proc Natl Acad Sci USA 99:6567-6572). The program was used to identify specific subsets of fluorescence data that best characterize each class and thus serve as significant diagnostic indicators. Briefly, the method computed a standardized centroid for each class. This is the average fluorescence for protein in each class divided by the within-class standard deviation for that protein. Centroids were “shrunken”—reduced by a threshold value—to reduce error and outlier effect. The microarray fluorescence of each new sample was then compared to each shrunken class centroid; the class whose centroid that it was closest to, in squared distance, was the predicted class for that new sample. Using this information, PAM generated a list of proteins presented in order of diagnostic significance.

PAM was used to produce a list of the top fifty most important proteins for distinguishing Alzheimer's Disease sera from Control Sera which is shown below in Table 6.

TABLE 6 Protein AD Control database ID Description score score BC030984.1 cDNA clone MGC: 32654 IMAGE: 4701898, 0.2132 −0.2665 complete cds PHR5001 Recombinant human CTLA-4/Fc 0.2108 −0.2635 BC016380.1 cDNA clone MGC: 27376 IMAGE: 4688477, 0.1766 −0.2208 complete cds BC015833.1 cDNA clone MGC: 27152 IMAGE: 4691630, 0.1621 −0.2026 complete cds BC099907.1 General transcription factor II-I −0.156 0.195 BC051695.1 FERM domain containing 8 (FRMD8) 0.1452 −0.1816 BC040106.1 hypothetical protein HSPC111 (HSPC111) 0.1429 −0.1787 NM_003141.2 tripartite motif-containing 21 (TRIM21) 0.1388 −0.1735 NM_003384.1 vaccinia related kinase 1 (VRK1) 0.1268 −0.1585 BC004236.2 ubiquitin-conjugating enzyme E2S (UBE2S) 0.1244 −0.1555 BC001662.1 MAP kinase-activated protein kinase 3 0.1183 −0.1479 NM_017588.1 WD repeat domain 5 (WDR5), transcript variant 1 0.1176 −0.147 NM_032377.2 elongation factor 1 homolog (S. cerevisiae) (ELOF1) 0.1158 −0.1448 NM_021032.2 fibroblast growth factor 12 (FGF12), transcript 0.1144 −0.143 variant 1 NM_000984.2 ribosomal protein L23a (RPL23A) 0.1123 −0.1403 BC064984.1 additional sex combs like 1 (Drosophila) (ASXL1) 0.1106 −0.1383 NM_012387.1 peptidyl arginine deiminase, type IV (PADI4) 0.1082 −0.1353 NM_001641.2 APEX nuclease (multifunctional DNA repair 0.1062 −0.1327 enzyme) 1 (APEX1), transcript variant 1 NM_001896.2 casein kinase 2, alpha prime polypeptide (CSNK2A2) 0.1045 −0.1306 NM_014481.2 APEX nuclease (apurinic/apyrimidinic endonuclease) −0.1009 0.1261 2 (APEX2), nuclear gene encoding mitochondrial protein NM_014280.1 DnaJ homolog subfamily C member 8 0.0993 −0.1242 BC007228.1 CSAG family, member 3A (CSAG3A) 0.0952 −0.119 BC021174.1 Small EDRK-rich factor 1 0.0924 −0.1155 BC021174.1 Small EDRK-rich factor 1 0.0924 −0.1155 BC033758.1 centaurin, alpha 2 (CENTA2) 0.0894 −0.1118 BC005248.1 eukaryotic translation initiation factor 1A, Y-linked 0.0876 −0.1096 (EIF1AY) BC022098.1 cDNA clone MGC: 31944 IMAGE: 4878869, 0.0853 −0.1066 complete cds NM_024754.2 pentatricopeptide repeat domain 2 (PTCD2) 0.0845 −0.1057 NM_024316.1 leukocyte receptor cluster (LRC) member 1 (LENG1) −0.0836 0.1044 NM_015920.3 40S ribosomal protein S27-like protein 0.0798 −0.0997 BC048970.1 tubulin tyrosine ligase-like family, member 7 0.0792 −0.099 (TTLL7) NM_003668.2 mitogen-activated protein kinase-activated protein 0.0789 −0.0986 kinase 5 (MAPKAPK5), transcript variant 1 NM_007278.1 GABA(A) receptor-associated protein (GABARAP) 0.0787 −0.0984 NM_006838.1 methionyl aminopeptidase 2 (METAP2) 0.0779 −0.0974 NM_018439.1 Impact homolog (mouse) (IMPACT) 0.0772 −0.0965 NM_002013.2 FK506 binding protein 3, 25 kDa (FKBP3) 0.0749 −0.0937 NM_018956.2 chromosome 9 open reading frame 9 (C9orf9) 0.0744 −0.093 NM_004987.3 LIM and senescent cell antigen-like-containing −0.0741 0.0926 domain protein 1 BC004292.1 PHD finger protein 15 (PHF15) −0.0709 0.0886 NM_133494.1 NIMA (never in mitosis gene a)-related kinase 7 0.0699 −0.0874 (NEK7) NM_145063.1 chromosome 6 open reading frame 130 (C6orf130) 0.0646 −0.0808 NM_021104.1 ribosomal protein L41 (RPL41), transcript variant 1 0.0645 −0.0807 NM_006223.1 protein (peptidylprolyl cis/trans isomerase) NIMA- 0.0633 −0.0791 interacting, 4 (parvulin) (PIN4) NM_003135.1 Signal recognition particle 19 kDa protein 0.0622 −0.0777 NM_015933.1 coiled-coil domain containing 72 (CCDC72) 0.0615 −0.0769 NM_001031.4 40S ribosomal protein S28 0.0606 −0.0758 BC022524.1 fibroblast growth factor 12 (FGF12) 0.0594 −0.0743 NM_001028.2 ribosomal protein S25 (RPS25) 0.0578 −0.0722 NM_001997.2 Finkel-Biskis-Reilly murine sarcoma virus (FBR- 0.0572 −0.0715 MuSV) ubiquitously expressed (FAU) NM_080659.1 chromosome 11 open reading frame 52 (C11orf52) 0.0566 −0.0707

Random Forest

The third quantitative method that was used to corroborate the results was Random Forest. This is an open-source classification algorithm, run through R, that uses an ensemble of decision-making trees. Each of these classification trees was built using a bootstrap sample of the data, and at each split the candidate set of variables was a random subset. Random Forest directly returned several measures of variable significance, which were related to the relevance of the variable in the classification. Hence, in this case, it provided an evaluation of each protein's relative importance to proper diagnosis.

The most reliable measure was based on the decrease of classification accuracy when values of a variable in a node of a tree were permuted randomly and this was the measure of variable importance. Another estimation of significance of a variable was based on Gini impurity. Every time a split of a node was made on variable m the Gini impurity criterion for the two descendent nodes was less than the parent node. Adding up the Gini decreases for each individual variable over all trees in the forest gave a fast variable importance that is often very consistent with the permutation importance measure.

The Relative Fluorescence Unit value for each protein spot on the microarray, as calculated by Genepix Pro and Prospector, was imported into Random Forest. The prediction model was performed using the R package and all default settings—as is proscribed for the best microarray analysis results. Calculating an average Out-Of-Bag Error of only 6.67%, the algorithm was able to quickly evaluate protein significance based on the evaluation methods described above.

Results

Three different, unbiased statistical methods were used to evaluate the diagnostic significance of individual autoantibodies in the microarray data and they reflected one another almost perfectly. The three resultant lists considered the same autoantibodies diagnostically important, and assigned them similar significance. The shared conclusions of all three lend the results great confidence. The list of all of the protein antigens determined by these methods that have autoantibodies that can be used as indicators for Alzheimer's disease is shown below in Table 7. Included is the protein database identification number, the open reading frame number, the common name for each protein, its disease-state indication, and the relevant p-value as calculated by the M-statistic.

TABLE 7 Ultimate Database ID ORF ID Description Indication P-Value NM_024754.2 IOH12500 pentatricopeptide repeat domain 2 AD 8.03E−14 (PTCD2) BC051695.1 IOH26532 FERM domain containing 8 AD 4.06E−13 (FRMD8) NM_014280.1 IOH42939 DnaJ homolog subfamily C AD 9.49E−12 member 8 BC064984.1 IOH40665 additional sex combs like 1 AD 6.02E−11 (Drosophila) (ASXL1) BC030814.1 IOH23035 immunoglobulin kappa variable 1- Control 7.00E−11 5 (IGKV1-5) NM_003384.1 IOH41408 vaccinia related kinase 1 (VRK1) AD 2.03E−10 NM_001544.2 IOH23172 intercellular adhesion molecule 4 AD 2.03E−10 (Landsteiner-Wiener blood group) (ICAM4), transcript variant 1 NM_001896.2 IOH6369 casein kinase 2, alpha prime AD 2.51E−10 polypeptide (CSNK2A2) NM_021104.1 IOH13630 ribosomal protein L41 (RPL41), AD 4.61E−10 transcript variant 1 BC016380.1 IOH23077 cDNA clone MGC: 27376 AD 5.14E−10 IMAGE: 4688477, complete cds NM_012387.1 IOH11317 peptidyl arginine deiminase, type AD 6.53E−10 IV (PADI4) NM_003135.1 IOH59899 Signal recognition particle 19 kDa AD 8.77E−10 protein BC022524.1 IOH10757 fibroblast growth factor 12 AD 8.77E−10 (FGF12) BC000758.1 IOH3735 Coiled-coil domain-containing AD 1.45E−09 protein 28A NM_021032.2 IOH35339 fibroblast growth factor 12 AD 1.45E−09 (FGF12), transcript variant 1 NM_022343.2 IOH59950 Golgi-associated plant AD 1.49E−09 pathogenesis-related protein 1 BC004236.2 IOH3887 ubiquitin-conjugating enzyme E2S AD 2.00E−09 (UBE2S) NM_000983.3 IOH58958 60S ribosomal protein L22 AD 2.05E−09 NM_017588.1 IOH4895 WD repeat domain 5 (WDR5), AD 2.88E−09 transcript variant 1 NM_018956.2 IOH11209 chromosome 9 open reading frame AD 3.30E−09 9 (C9orf9) BC033178.1 IOH23236 immunoglobulin heavy constant AD 4.07E−09 gamma 3 (G3m marker) (IGHG3) NM_006628.4 IOH3044 cyclic AMP phosphoprotein, 19 kD AD 4.19E−09 (ARPP-19) BC022098.1 IOH14790 cDNA clone MGC: 31944 AD 4.19E−09 IMAGE: 4878869, complete cds NM_001641.2 IOH5081 APEX nuclease (multifunctional AD 5.85E−09 DNA repair enzyme) 1 (APEX1), transcript variant 1 NM_003668.2 mitogen-activated protein kinase- AD 8.91E−09 activated protein kinase 5 (MAPKAPK5), transcript variant 1 NM_015933.1 IOH3769 coiled-coil domain containing 72 AD 8.91E−09 (CCDC72) PHC1244 chemokine (C-C motif) ligand 19 AD 9.85E−09 (CCL19) BC099907.1 IOH62625 General transcription factor II-I Control 1.09E−08 BC007782.2 IOH6514 immunoglobulin lambda constant AD 1.09E−08 1 (Mcg marker) (IGLC1) BC006423.1 Serine/threonine-protein kinase 6 AD 1.34E−08 BC042628.1 IOH27650 serpin peptidase inhibitor, clade E AD 1.34E−08 (nexin, plasminogen activator inhibitor type 1), member 2 (SERPINE2) BC021561.1 IOH14131 FACT complex subunit SPT16 AD 1.34E−08 BC005248.1 IOH7358 eukaryotic translation initiation AD 1.34E−08 factor 1A, Y-linked (EIF1AY) NM_006223.1 IOH7192 protein (peptidylprolyl cis/trans AD 1.34E−08 isomerase) NIMA-interacting, 4 (parvulin) (PIN4) NM_032377.2 IOH6191 elongation factor 1 homolog (S. cerevisiae) AD 1.34E−08 (ELOF1) BC057774.1 IOH29168 RNA (guanine-9-)- AD 1.52E−08 methyltransferase domain- containing protein 3 NM_004196.2 Cyclin-dependent kinase-like 1 AD 1.64E−08 BC001662.1 MAP kinase-activated protein AD 2.32E−08 kinase 3 NM_015920.3 IOH57353 40S ribosomal protein S27-like AD 2.32E−08 protein NM_001031.4 IOH58930 40S ribosomal protein S28 AD 2.62E−08 NM_003688.1 Peripheral plasma membrane AD 2.62E−08 protein CASK BC048970.1 IOH26893 tubulin tyrosine ligase-like family, AD 3.23E−08 member 7 (TTLL7) NM_000984.2 IOH13591 ribosomal protein L23a (RPL23A) AD 3.23E−08 NM_018439.1 IOH23069 Impact homolog (mouse) AD 3.76E−08 (IMPACT) NM_002305.2 IOH3861 lectin, galactoside-binding, AD 3.76E−08 soluble, 1 (galectin 1) (LGALS1) BC056508.1 IOH29456 variable charge, Y-linked 1B AD 4.13E−08 (VCY) BC090938.1 IOH62696 Ig gamma-1 chain C region AD 4.45E−08 NM_002013.2 IOH14109 FK506 binding protein 3, 25 kDa AD 4.51E−08 (FKBP3) NM_007278.1 IOH41289 GABA(A) receptor-associated AD 4.51E−08 protein (GABARAP) BC007228.1 IOH6059 CSAG family, member 3A AD 4.51E−08 (CSAG3A) BC033758.1 IOH21879 centaurin, alpha 2 (CENTA2) AD 5.27E−08 BC092518.1 IOH62695 Ig gamma-1 chain C region AD 6.86E−08 BC019598.1 IOH10613 Zinc finger matrin-type protein 4 AD 7.00E−08 NM_145909.1 IOH45888 Zinc finger protein 323 AD 7.00E−08 NM_003516.2 IOH4867 histone cluster 2, H2aa3 AD 7.22E−08 (HIST2H2AA3) NM_006838.1 IOH11106 methionyl aminopeptidase 2 AD 7.36E−08 (METAP2) BC026038.1 IOH13982 Ig gamma-1 chain C region AD 1.01E−07 NM_002129.2 IOH3826 high-mobility group box 2 AD 1.01E−07 (HMGB2) NM_002677.1 IOH27101 peripheral myelin protein 2 AD 1.16E−07 (PMP2) BC001132.1 IOH3853 DEAD (Asp-Glu-Ala-Asp) box AD 1.27E−07 polypeptide 54 (DDX54) NM_001001794.1 IOH27259 family with sequence similarity AD 1.27E−07 116, member B (FAM116B) NM_001997.2 IOH1655 Finkel-Biskis-Reilly murine AD 1.27E−07 sarcoma virus (FBR-MuSV) ubiquitously expressed (FAU) BC021174.1 IOH10706 Small EDRK-rich factor 1 AD 1.27E−07 NM_001028.2 IOH5471 ribosomal protein S25 (RPS25) AD 1.27E−07 NM_003512.3 IOH14485 Histone H2A type 1-C AD 1.78E−07 NM_002095.1 IOH22963 general transcription factor IIE, AD 1.97E−07 polypeptide 2, beta 34 kDa (GTF2E2) NM_005720.1 IOH3992 actin related protein 2/3 complex, AD 1.97E−07 subunit 1B, 41 kDa (ARPC1B) NM_003868.1 IOH42157 fibroblast growth factor 16 AD 1.97E−07 (FGF16) NM_004214.3 IOH2103 fibroblast growth factor (acidic) AD 1.97E−07 intracellular binding protein (FIBP), transcript variant 2 NM_021079.2 IOH14141 N-myristoyltransferase 1 (NMT1) AD 1.99E−07 NM_015833.1 IOH38242 adenosine deaminase, RNA- AD 2.62E−07 specific, B1 (RED1 homolog rat) (ADARB1), transcript variant 2 PHR5001 Recombinant human CTLA-4/Fc AD 2.62E−07 BC030983.1 IOH23183 immunoglobulin lambda locus AD 2.62E−07 (IGL@) BC030984.1 IOH23182 cDNA clone MGC: 32654 AD 2.62E−07 IMAGE: 4701898, complete cds BC002733.2 IOH5365 chromosome 1 open reading frame Control 2.62E−07 77 (C1orf77) NM_133494.1 IOH45126 NIMA (never in mitosis gene a)- AD 2.65E−07 related kinase 7 (NEK7) BC010467.1 IOH11119 cDNA clone MGC: 17410 AD 3.42E−07 IMAGE: 4156035, complete cds NM_014060.1 IOH4208 malignant T cell amplified AD 3.42E−07 sequence 1 (MCTS1) NM_016167.3 IOH40609 nucleolar protein 7, 27 kDa AD 3.81E−07 (NOL7) BC015833.1 IOH14840 cDNA clone MGC: 27152 AD 4.30E−07 IMAGE: 4691630, complete cds NM_145063.1 IOH13839 chromosome 6 open reading frame AD 5.08E−07 130 (C6orf130) BC040106.1 IOH26285 hypothetical protein HSPC111 AD 5.08E−07 (HSPC111) BC010947.1 IOH14455 signal recognition particle 19 kDa AD 5.08E−07 (SRP19) NM_014065.2 IOH43942 Protein asteroid homolog 1 AD 5.31E−07 BC012760.2 IOH62834 Glycogen synthase kinase-3 beta AD 5.38E−07 NM_004088.1 IOH11297 deoxynucleotidyltransferase, AD 6.41E−07 terminal (DNTT), transcript variant 1 BC019337.1 IOH12297 immunoglobulin heavy constant AD 7.15E−07 gamma 1 (G1m marker) (IGHG1) NM_024316.1 IOH12150 leukocyte receptor cluster (LRC) Control 7.80E−07 member 1 (LENG1) NM_002938.2 IOH41414 ring finger protein 4 (RNF4) AD 7.80E−07 NM_006620.2 IOH4029 HBS1-like (S. cerevisiae) AD 8.79E−07 (HBS1L) NM_000992.2 IOH1702 60S ribosomal protein L29 AD 1.05E−06 NM_024668.2 IOH46162 ankyrin repeat and KH domain AD 1.05E−06 containing 1 (ANKHD1), transcript variant 3 NM_031445.1 IOH5185 AMME chromosomal region gene AD 1.26E−06 1-like (AMMECR1L) NM_003517.2 IOH29296 histone cluster 2, H2ac AD 1.38E−06 (HIST2H2AC) BC072419.1 IOH62555 Ig gamma-1 chain C region AD 1.50E−06 NM_145174.1 IOH44767 DnaJ (Hsp40) homolog, subfamily AD 1.57E−06 B, member 7 (DNAJB7) BC022361.1 IOH14170 rRNA-processing protein FCF1 AD 1.57E−06 homolog BC006376.1 IOH6481 N-myristoyltransferase 2 (NMT2) AD 1.60E−06 NM_001895.1 casein kinase 2, alpha 1 AD 1.60E−06 polypeptide (CSNK2A1), transcript variant 2 NM_003524.2 IOH58715 Histone H2B type 1-H AD 1.69E−06 BC027951.1 IOH11889 Cas scaffolding protein family AD 1.93E−06 member 4 NM_134427.1 IOH45474 regulator of G-protein signaling 3 AD 2.02E−06 (RGS3), transcript variant 4 NM_052969.1 IOH12514 ribosomal protein L39-like AD 2.02E−06 (RPL39L) NM_023080.1 IOH13369 chromosome 8 open reading frame AD 2.17E−06 33 (C8orf33) NM_138779.1 IOH10711 chromosome 13 open reading AD 2.17E−06 frame 27 (C13orf27) BC026030.1 IOH14611 zinc finger protein 239 (ZNF239) AD 2.32E−06 BC029760.1 IOH22119 OTU domain containing 6B AD 2.76E−06 (OTUD6B) PHC1475 C-C motif chemokine 21 AD 3.00E−06 NM_133336.1 IOH42549 Wolf-Hirschhorn syndrome AD 3.44E−06 candidate 1 (WHSC1), transcript variant 9 BC034142.1 IOH23177 immunoglobulin kappa variable 1- AD 3.67E−06 5 (IGKV1-5) NM_020235.2 IOH44025 bobby sox homolog (Drosophila) AD 3.67E−06 (BBX) NM_198829.1 IOH58974 Ras-related C3 botulinum toxin AD 3.89E−06 substrate 1 BC098112.1 IOH63324 Histone H2B type 1-N AD 3.89E−06 NM_032359.1 IOH5762 chromosome 3 open reading frame AD 4.32E−06 26 (C3orf26) NM_001966.2 IOH62346 Peroxisomal bifunctional enzyme AD 4.32E−06 BC032451.1 IOH21663 cDNA clone MGC: 40426 AD 4.76E−06 IMAGE: 5178085, complete cds XM_379117.1 IOH43619 PREDICTED: Homo sapiens AD 4.98E−06 hypothetical protein LOC150568 (LOC150568) BC033159.1 IOH23223 DnaJ (Hsp40) homolog, subfamily AD 4.98E−06 C, member 8 (DNAJC8) NM_006756.2 IOH42106 transcription elongation factor A AD 4.98E−06 (SII), 1 (TCEA1), transcript variant 1 NM_016940.1 IOH12821 RWD domain containing 2B AD 5.00E−06 (RWDD2B) NM_177559.2 IOH13704 casein kinase 2, alpha 1 AD 5.00E−06 polypeptide (CSNK2A1), transcript variant 1 NM_004178.3 IOH45867 TAR (HIV-1) RNA binding AD 5.13E−06 protein 2 (TARBP2), transcript variant 3 NM_032338.2 IOH7537 chromosome 12 open reading AD 5.22E−06 frame 31 (C12orf31) BC005955.1 IOH7485 chromosome 8 open reading frame AD 5.50E−06 53 (C8orf53) NM_001009613.1 IOH58584 Sperm protein associated with the AD 5.50E−06 nucleus on the X chromosome N4 BC036723.1 IOH22599 Fc fragment of IgG, low affinity AD 5.50E−06 IIIa, receptor (CD16a) (FCGR3A) NM_003690.3 IOH57108 Interferon-inducible double AD 6.84E−06 stranded RNA-dependent protein kinase activator A NM_014473.2 IOH9851 DIM1 dimethyladenosine AD 6.91E−06 transferase 1-like (S. cerevisiae) (DIMT1L) NM_032855.1 IOH14623 hematopoietic SH2 domain AD 7.69E−06 containing (HSH2D) NM_001167.2 IOH21984 baculoviral IAP repeat-containing AD 7.69E−06 4 (BIRC4) NM_178571.2 IOH26524 hypothetical protein MGC51025 AD 7.69E−06 (MGC51025) NM_003600.1 aurora kinase A (AURKA), AD 7.69E−06 transcript variant 2 NM_006912.3 IOH29584 Ras-like without CAAX 1 (RIT1) AD 8.05E−06 NM_005307.1 G protein-coupled receptor kinase 4 AD 8.29E−06 BC001280.1 IOH21165 Serine/threonine-protein kinase 6 AD 8.71E−06 NM_182970.2 IOH43687 regulating synaptic membrane AD 8.71E−06 exocytosis 4 (RIMS4) NM_153332.2 IOH27323 three prime histone mRNA AD 8.71E−06 exonuclease 1 (THEX1) NM_139016.2 IOH27635 chromosome 20 open reading AD 8.88E−06 frame 198 (C20orf198) NM_003677.3 IOH56971 Density-regulated protein AD 1.15E−05 NM_013293.1 IOH9999 Transformer-2 protein homolog AD 1.15E−05 NM_014481.2 IOH4887 APEX nuclease Control 1.17E−05 (apurinic/apyrimidinic endonuclease) 2 (APEX2), nuclear gene encoding mitochondrial protein BC033856.1 IOH21797 La ribonucleoprotein domain AD 1.18E−05 family, member 1 (LARP1) NM_000939.1 IOH40048 proopiomelanocortin AD 1.18E−05 (adrenocorticotropin/beta- lipotropin/alpha-melanocyte stimulating hormone/beta- melanocyte stimulating hormone/ beta-endorphin) (POMC), transcript variant 2 BC009348.2 IOH12064 cirrhosis, autosomal recessive 1A AD 1.29E−05 (cirhin) (CIRH1A) NM_014508.2 IOH54737 apolipoprotein B mRNA editing AD 1.46E−05 enzyme, catalytic polypeptide-like 3C (APOBEC3C), mRNA. NM_080659.1 IOH7410 chromosome 11 open reading AD 1.48E−05 frame 52 (C11orf52) NM_022755.2 IOH10937 inositol 1,3,4,5,6- AD 1.54E−05 pentakisphosphate 2-kinase (IPPK) NM_002690.1 IOH41443 polymerase (DNA directed), beta AD 1.57E−05 (POLB) BC011668.1 Casein kinase II subunit alpha AD 1.57E−05 NM_002128.2 IOH2937 high-mobility group box 1 AD 1.62E−05 (HMGB1) BC012472.1 IOH11069 ubiquitin D (UBD) AD 1.62E−05 BC030020.2 IOH22410 DEAD (Asp-Glu-Ala-Asp) box AD 1.62E−05 polypeptide 55 (DDX55) BC018060.1 IOH11303 Ras-like without CAAX 2 (RIT2) AD 1.62E−05 NM_003141.2 IOH9948 tripartite motif-containing 21 AD 1.62E−05 (TRIM21) NM_007054.1 IOH26900 kinesin family member 3A AD 1.62E−05 (KIF3A) NM_006924.3 IOH11039 splicing factor, arginine/serine- AD 1.67E−05 rich 1 (splicing factor 2, alternate splicing factor) (SFRS1), transcript variant 1 NM_032563.1 IOH40397 late cornified envelope 3D AD 1.67E−05 (LCE3D) NM_173080.1 IOH34934 small proline-rich protein 4 AD 1.67E−05 (SPRR4) NM_003527.4 IOH58710 Histone H2B type 1-O AD 1.82E−05 BC009762.2 IOH14113 Tripartite motif-containing protein AD 1.82E−05 41 NM_006861.2 IOH10011 RAB35, member RAS oncogene AD 1.83E−05 family (RAB35) NM_002136.1 IOH3526 heterogeneous nuclear AD 1.90E−05 ribonucleoprotein A1 (HNRNPA1), transcript variant 1 BC009623.1 IOH9844 nucleophosmin (nucleolar AD 2.11E−05 phosphoprotein B23, numatrin) (NPM1) NM_021063.2 IOH58956 Histone H2B type 1-D AD 2.11E−05 BC054021.1 IOH29457 pterin-4 alpha-carbinolamine AD 2.29E−05 dehydratase/dimerization cofactor of hepatocyte nuclear factor 1 alpha (TCF1) 2 (PCBD2) NM_012108.1 IOH13463 signal transducing adaptor family AD 2.63E−05 member 1 (STAP1) NM_023937.1 IOH4594 mitochondrial ribosomal protein AD 3.15E−05 L34 (MRPL34), nuclear gene encoding mitochondrial protein XM_088679.2 IOH43003 Spermatid nuclear transition AD 3.33E−05 protein 4 NM_022720.5 IOH52788 DiGeorge syndrome critical region AD 3.33E−05 gene 8 (DGCR8) NM_016073.2 IOH10649 hepatoma-derived growth factor, AD 3.33E−05 related protein 3 (HDGFRP3) NM_018105.1 IOH10776 THAP domain containing, AD 3.41E−05 apoptosis associated protein 1 (THAP1), transcript variant 1 NM_005371.2 IOH4172 methyltransferase like 1 AD 3.56E−05 (METTL1), transcript variant 1 BC029427.1 IOH23192 coiled-coil domain containing 23 AD 3.61E−05 (CCDC23) NM_032476.1 IOH13845 mitochondrial ribosomal protein AD 3.66E−05 S6 (MRPS6), nuclear gene encoding mitochondrial protein NM_014110.3 IOH39485 protein phosphatase 1, regulatory Control 3.66E−05 (inhibitor) subunit 8 (PPP1R8), transcript variant 1 NM_003089.4 IOH40192 small nuclear ribonucleoprotein AD 3.88E−05 70 kDa polypeptide (RNP antigen) (SNRP70) BC020972.1 Casein kinase I isoform gamma-2 AD 3.88E−05 BC000381.2 IOH3454 TBP-like 1 (TBPL1) AD 3.88E−05 NM_007285.5 IOH7450 GABA(A) receptor-associated AD 3.99E−05 protein-like 2 (GABARAPL2) NM_004060.2 IOH4393 cyclin G1 (CCNG1), transcript AD 4.02E−05 variant 1 BC001780.1 IOH4955 Uncharacterized methyltransferase AD 4.02E−05 WBSCR22 NM_022048.1 IOH21026 casein kinase 1, gamma 1 AD 4.02E−05 (CSNK1G1) BC035256.1 IOH27660 Putative adenylate kinase 7 AD 4.19E−05 NM_175887.2 IOH27336 proline rich 15 (PRR15) AD 4.22E−05 BC010919.1 IOH27800 ribosomal protein L35 (RPL35) AD 4.79E−05 NM_016207.2 IOH14059 cleavage and polyadenylation AD 5.24E−05 specific factor 3, 73 kDa (CPSF3) BC000784.1 IOH4711 baculoviral IAP repeat-containing AD 5.50E−05 5 (survivin) (BIRC5) NM_002364.1 IOH11315 melanoma antigen family B, 2 AD 5.50E−05 (MAGEB2) NM_022839.2 IOH1783 mitochondrial ribosomal protein AD 6.97E−05 S11 (MRPS11), nuclear gene encoding mitochondrial protein, transcript variant 1 NM_014370.2 IOH60262 SFRS protein kinase 3 (SRPK3) AD 6.97E−05 NM_016505.2 IOH6093 zinc finger, CCHC domain AD 7.25E−05 containing 17 (ZCCHC17) BC030813.1 IOH23055 cDNA clone MGC: 22645 AD 7.42E−05 IMAGE: 4700961, complete cds BC020803.1 IOH14817 developmentally regulated GTP AD 7.42E−05 binding protein 1 (DRG1) NM_205848.1 IOH43389 synaptotagmin VI (SYT6) AD 7.94E−05 NM_006398.2 IOH59996 Ubiquitin D AD 7.94E−05 NM_017646.3 IOH37769 tRNA isopentenyltransferase 1 AD 8.04E−05 (TRIT1) NM_006925.2 IOH58606 Splicing factor, arginine/serine- AD 8.04E−05 rich 5 NM_153822.1 IOH41107 proteasome (prosome, macropain) AD 8.43E−05 26S subunit, non-ATPase, 4 (PSMD4), transcript variant 2 NM_014321.2 IOH39827 origin recognition complex, AD 0.000103 subunit 6 like (yeast) (ORC6L) BC012876.1 IOH10177 Ig lambda chain C regions AD 0.000104 NM_021967.1 IOH45915 small EDRK-rich factor 1A AD 0.000104 (telomeric) (SERF1A) NM_003295.1 IOH25767 tumor protein, translationally- AD 0.000104 controlled 1 (TPT1) NM_017503.2 IOH12519 surfeit 2 (SURF2) AD 0.000105 BC018137.1 IOH10369 TATA box binding protein (TBP)- AD 0.000108 associated factor, RNA polymerase I, B, 63 kDa (TAF1B) BC005004.1 IOH4814 family with sequence similarity AD 0.000114 64, member A (FAM64A) NM_152373.2 IOH14361 zinc finger protein 684 (ZNF684) AD 0.000114 NM_000989.2 IOH3809 ribosomal protein L30 (RPL30) AD 0.000121 NM_000800.2 IOH21917 fibroblast growth factor 1 (acidic) AD 0.000121 (FGF1), transcript variant 1 NM_000975.2 IOH1740 ribosomal protein L11 (RPL11) AD 0.000142 BC064144.1 IOH40037 spermatogenesis associated 1 Control 0.000142 (SPATA1) PHC1695 C—X—C motif chemokine 11 AD 0.000151 NM_022140.2 IOH38016 Band 4.1-like protein 4A AD 0.000159 NM_016287.2 IOH43530 heterochromatin protein 1, binding AD 0.000162 protein 3 (HP1BP3) BC015586.2 IOH46065 laminin, gamma 1 (formerly AD 0.000162 LAMB2) (LAMC1) NM_023931.1 IOH3950 zinc finger protein 747 (ZNF747) AD 0.000168 NM_153207.2 IOH14301 AE binding protein 2 (AEBP2) AD 0.000168 NM_007079.2 IOH4497 Protein tyrosine phosphatase type AD 0.000168 IVA 3 NM_004397.3 IOH45655 Probable ATP-dependent RNA AD 0.000172 helicase DDX6 NM_012424.2 Ribosomal protein S6 kinase AD 0.000172 delta-1 CCP_1BSA NA Control 0.000177 NM_020239.2 IOH21482 CDC42 small effector 1 AD 0.000186 (CDC42SE1), transcript variant 2 BC029378.1 IOH23186 telomeric repeat binding factor AD 0.000186 (NIMA-interacting) 1 (TERF1) BC062732.1 IOH62856 Ig kappa chain C region Control 0.000211 BC000306.1 IOH3456 hydroxyacyl-Coenzyme A AD 0.000216 dehydrogenase (HADH) BC031650.1 IOH22742 Putative E3 ubiquitin-protein Control 0.000221 ligase SH3RF2 NM_182692.1 IOH38187 Serine/threonine-protein kinase AD 0.000227 SRPK2 NM_032350.3 IOH6347 Uncharacterized protein C7orf50 AD 0.000227 NM_001022.3 IOH4572 ribosomal protein S19 (RPS19) AD 0.000227 NM_001002913.1 IOH26561 peptidyl-tRNA hydrolase 1 AD 0.000227 homolog (S. cerevisiae) (PTRH1) BC000535.1 IOH4145 Suppressor of SWI4 1 homolog AD 0.000227 NM_017692.1 IOH4894 aprataxin (APTX), transcript AD 0.000233 variant 4 NM_000993.2 IOH14051 ribosomal protein L31 (RPL31), AD 0.000245 transcript variant 1 NM_152653.1 IOH13176 ubiquitin-conjugating enzyme E2E AD 0.000245 2 (UBC4/5 homolog, yeast) (UBE2E2) NM_014891.1 IOH4282 PDGFA associated protein 1 AD 0.000245 (PDAP1) NM_012148.1 IOH39321 double homeobox, 3 (DUX3) AD 0.000252 NM_024046.1 CaM kinase-like vesicle- AD 0.00028 associated (CAMKV) NM_022063.1 IOH27864 chromosome 10 open reading AD 0.00028 frame 84 (C10orf84) BC036434.1 IOH62212 Serine/threonine-protein kinase AD 0.00032 VRK2 NM_001396.2 Dual specificity tyrosine- AD 0.00032 phosphorylation-regulated kinase 1A NM_004939.1 IOH14578 DEAD (Asp-Glu-Ala-Asp) box AD 0.00032 polypeptide 1 (DDX1) NM_001039724.1 IOH63165 Nostrin AD 0.000331 NM_138551.1 IOH13700 thymic stromal lymphopoietin AD 0.000332 (TSLP), transcript variant 2 XM_379194.1 IOH43490 PREDICTED: Homo sapiens AD 0.000332 hypothetical LOC401068 (LOC401068) BC007401.2 IOH5852 cell division cycle 25 homolog A AD 0.00034 (S. pombe) (CDC25A) BC008902.2 IOH46064 GRIP and coiled-coil domain- AD 0.00034 containing protein 1 BC019039.2 IOH46089 Regulator of G-protein signaling 3 AD 0.000407 NM_016050.1 IOH4903 mitochondrial ribosomal protein AD 0.000432 L11 (MRPL11), nuclear gene encoding mitochondrial protein, transcript variant 1 NM_002927.3 IOH11040 regulator of G-protein signaling 13 AD 0.000432 (RGS13), transcript variant 1 NM_207430.1 IOH59509 FLJ46266 protein (FLJ46266), AD 0.000432 mRNA. NM_016508.2 IOH21339 Cyclin-dependent kinase-like 3 AD 0.000432 NM_197964.1 IOH7576 chromosome 7 open reading frame AD 0.000442 55 (C7orf55) BC021930.1 IOH13703 KIAA1530 protein (KIAA1530) AD 0.000442 NM_145043.1 IOH13260 nei like 2 (E. coli) (NEIL2) AD 0.000442 BC030586.2 IOH22241 signal transducing adaptor AD 0.000442 molecule (SH3 domain and ITAM motif) 1 (STAM) BC004292.1 IOH22899 PHD finger protein 15 (PHF15) Control 0.000442 BC022378.1 IOH13502 zinc finger with KRAB and SCAN AD 0.000443 domains 1 (ZKSCAN1) NM_003792.1 IOH10852 endothelial differentiation-related AD 0.000448 factor 1 (EDF1), transcript variant alpha BC070154.1 IOH63011 Non-histone chromosomal protein AD 0.000448 HMG-14 BC010074.2 IOH13694 FUS interacting protein AD 0.000479 (serine/arginine-rich) 1 (FUSIP1) NM_002201.3 IOH6793 interferon stimulated exonuclease AD 0.000479 gene 20 kDa (ISG20) BC033621.2 IOH21688 Pseudouridylate synthase 7 AD 0.000481 homolog-like protein NM_004114.2 IOH13832 fibroblast growth factor 13 AD 0.00054 (FGF13), transcript variant 1A NM_016483.3 IOH22255 PHD finger protein 7 (PHF7), AD 0.00054 transcript variant 1 NM_012420.1 IOH22625 interferon-induced protein with AD 0.000543 tetratricopeptide repeats 5 (IFIT5) NM_016203.2 IOH42382 protein kinase, AMP-activated, AD 0.000543 gamma 2 non-catalytic subunit (PRKAG2), transcript variant a, mRNA. NM_014878.2 IOH10030 Pumilio domain-containing AD 0.000544 protein KIAA0020 NM_018664.1 IOH44746 Jun dimerization protein p21SNFT AD 0.000593 (SNFT) NM_002402.1 IOH3706 mesoderm specific transcript AD 0.000613 homolog (mouse) (MEST), transcript variant 1 NM_003769.2 IOH41184 splicing factor, arginine/serine- AD 0.000613 rich 9 (SFRS9) NM_018132.3 IOH45979 centromere protein Q (CENPQ) AD 0.000613 NM_006072.4 IOH40395 chemokine (C-C motif) ligand 26 AD 0.000613 (CCL26) NM_021029.3 IOH4423 ribosomal protein L36a (RPL36A) AD 0.000638 NM_000978.2 IOH13951 ribosomal protein L23 (RPL23) AD 0.000638 NM_001023.2 IOH6083 ribosomal protein S20 (RPS20) AD 0.000638 BC013366.2 IOH27815 UNC-112 related protein 2 AD 0.000638 (URP2) BC001327.1 IOH3125 interferon-related developmental AD 0.000644 regulator 2 (IFRD2) BC000522.1 IOH3622 serpin peptidase inhibitor, clade F AD 0.000644 (alpha-2 antiplasmin, pigment epithelium derived factor), member 1 (SERPINF1) NM_019067.1 IOH13693 guanine nucleotide binding AD 0.000644 protein-like 3 (nucleolar)-like (GNL3L) NM_152634.1 IOH21490 TFS2-M domain-containing AD 0.000644 protein 1 (MGC17403) BC011842.2 IOH14099 hypothetical protein FLJ11184 AD 0.00065 (FLJ11184) BC068514.1 IOH40543 NF-kappaB repressing factor AD 0.00065 (NKRF) NM_018063.3 IOH44165 helicase, lymphoid-specific AD 0.000661 (HELLS) NM_198467.1 IOH40427 round spermatid basic protein 1- AD 0.000739 like (RSBN1L) NM_198517.2 IOH25922 TBC1 domain family, member AD 0.000835 10C (TBC1D10C) NM_001564.1 IOH22913 inhibitor of growth family, AD 0.000835 member 2 (ING2) NM_002930.1 IOH54792 GTP-binding protein Rit2 AD 0.000835 NM_019058.1 IOH6497 DNA-damage-inducible transcript AD 0.000835 4 protein NM_020661.1 IOH6382 activation-induced cytidine AD 0.000868 deaminase (AICDA) NM_144659.1 IOH21795 t-complex 10 (mouse)-like Control 0.000868 (TCP10L) NM_173822.1 IOH27491 family with sequence similarity AD 0.000898 126, member B (FAM126B) BC056887.1 IOH29097 chromosome 5 open reading frame AD 0.000898 5 (C5orf5) BC070334.1 IOH40810 immunoglobulin kappa constant AD 0.000898 (IGKC) NM_004071.1 Dual specificity protein kinase AD 0.000898 CLK1 XM_378514.1 IOH42688 PREDICTED: Homo sapiens Control 0.000901 hypothetical protein LOC283663 (LOC283663), mRNA NM_005801.2 IOH6916 eukaryotic translation initiation AD 0.000906 factor 1 (EIF1) BC001487.2 IOH12155 TAR DNA-binding protein 43 AD 0.000906 NM_006790.1 IOH7249 myotilin (MYOT) AD 0.000906 NM_175923.2 IOH22051 hypothetical protein MGC42630 AD 0.000906 (MGC42630) NM_000122.1 IOH6320 excision repair cross- AD 0.000918 complementing rodent repair deficiency, complementation group 3 (xeroderma pigmentosum group B complementing) (ERCC3) NM_001819.1 IOH3444 chromogranin B (secretogranin 1) Control 0.000992 (CHGB) BC010501.1 IOH10253 Catenin delta-1 AD 0.001011 BC005298.1 IOH7271 cyclin-dependent kinase 7 (MO15 AD 0.001015 homolog, Xenopus laevis, cdk- activating kinase) (CDK7) PHC0076 interleukin 7 (IL7) AD 0.001041 NM_138349.2 IOH45741 Tumor protein p53-inducible AD 0.001041 protein 13 BC000044.1 IOH4604 Spindlin-2B AD 0.001041 NM_014747.2 IOH4568 regulating synaptic membrane AD 0.001117 exocytosis 3 (RIMS3) NM_001014.2 IOH4063 ribosomal protein S10 (RPS10) AD 0.001122 NM_005678.3 IOH45840 SNRPN upstream reading frame AD 0.001122 (SNURF), transcript variant 1 BC010876.1 IOH9862 nei endonuclease VIII-like 1 (E. coli) AD 0.001122 (NEIL1) BC025281.1 IOH14071 RNA binding motif protein 9 AD 0.001147 (RBM9) NM_001013.2 IOH5840 ribosomal protein S9 (RPS9) AD 0.001147 NM_015414.2 IOH4985 ribosomal protein L36 (RPL36), AD 0.001201 transcript variant 2 NM_017566.2 IOH11408 kelch domain containing 4 AD 0.001209 (KLHDC4) BC015818.1 IOH14254 lectin, galactoside-binding, AD 0.001262 soluble, 8 (galectin 8) (LGALS8) BC036109.1 IOH27253 SECIS binding protein 2 AD 0.001265 (SECISBP2) NM_005738.1 IOH5077 ADP-ribosylation factor-like 4A AD 0.001498 (ARL4A), transcript variant 1 BC022816.1 IOH14672 NA AD 0.001498 NM_024303.1 IOH5245 zinc finger and SCAN domain AD 0.001533 containing 5 (ZSCAN5) BC018823.2 IOH14860 splicing factor, arginine/serine- AD 0.001533 rich 5 (SFRS5) NM_024319.1 IOH5397 chromosome 1 open reading frame AD 0.001533 35 (C1orf35) PV3359 Ephrin receptor A3 (EPHA3), AD 0.00166 transcript variant 1 BC006318.1 IOH6433 erythrocyte membrane protein Control 0.001674 band 4.9 (dematin) (EPB49) NM_145899.1 IOH6516 high mobility group AT-hook 1 AD 0.001732 (HMGA1), transcript variant 1 NM_021158.1 tribbles homolog 3 (Drosophila) AD 0.001796 (TRIB3) NM_005794.2 IOH41302 dehydrogenase/reductase (SDR AD 0.001796 family) member 2 (DHRS2), transcript variant 2 BC005807.2 IOH6261 stearoyl-CoA desaturase (delta-9- AD 0.001796 desaturase) (SCD) NM_006374.2 IOH6735 serine/threonine kinase 25 (STE20 AD 0.001796 homolog, yeast) (STK25) NM_152757.1 IOH43336 Putative uncharacterized protein AD 0.001796 C20orf200 NM_001009880.1 IOH42078 chromosome 22 open reading AD 0.001796 frame 9 (C22orf9), transcript variant 2 NM_138558.1 IOH13759 protein phosphatase 1, regulatory AD 0.001796 (inhibitor) subunit 8 (PPP1R8), transcript variant 2 BC007852.1 Serine/threonine-protein kinase 25 AD 0.001796 NM_012396.1 IOH12626 pleckstrin homology-like domain, AD 0.001845 family A, member 3 (PHLDA3) NM_012437.2 IOH3724 SNAP-associated protein AD 0.001845 (SNAPAP) PHC0205 interleukin 20 (IL20) AD 0.001845 NM_016093.2 IOH14674 ribosomal protein L26-like 1 AD 0.001845 (RPL26L1) NM_005902.1 IOH27044 SMAD family member 3 AD 0.001845 (SMAD3) XM_375456.2 IOH43380 Ataxin-7-like protein 3 AD 0.001925 NM_006275.2 IOH3168 splicing factor, arginine/serine- AD 0.00196 rich 6 (SFRS6) NM_018037.1 IOH45458 Ral GEF with PH domain and Control 0.001993 SH3 binding motif 2 (RALGPS2), transcript variant 1 BC011600.1 IOH13680 cDNA clone IMAGE: 3050953, AD 0.002095 **** WARNING: chimeric clone **** NM_014570.2 IOH5693 ADP-ribosylation factor GTPase AD 0.002095 activating protein 3 (ARFGAP3) NM_022551.2 IOH41520 ribosomal protein S18 (RPS18) AD 0.002095 BC063275.1 IOH40423 eukaryotic translation initiation AD 0.002095 factor 2C, 1 (EIF2C1) BC062423.1 IOH40739 chromosome 7 open reading frame AD 0.0021 41 (C7orf41) NM_170676.2 IOH26710 Meis homeobox 2 (MEIS2), Control 0.002174 transcript variant d BC096708.1 IOH63336 Wilms tumor-associated protein AD 0.002181 NM_199123.1 IOH42083 SET domain containing 3 AD 0.002181 (SETD3), transcript variant 2 BC010907.1 IOH12088 PAK1 interacting protein 1 AD 0.002181 (PAK1IP1) NM_004217.1 aurora kinase B (AURKB) AD 0.002181 NM_005737.3 IOH44753 ADP-ribosylation factor-like 4C AD 0.002186 (ARL4C) NM_020467.2 IOH3994 small trans-membrane and AD 0.002186 glycosylated protein (LOC57228), transcript variant 2 BC021180.2 IOH11041 high-mobility group box 4 AD 0.002209 (HMGB4) NM_004728.2 IOH46173 DEAD (Asp-Glu-Ala-Asp) box AD 0.002209 polypeptide 21 (DDX21) BC030702.1 IOH22356 microcephaly, primary autosomal AD 0.002281 recessive 1 (MCPH1) NM_003724.1 IOH26418 jerky homolog (mouse) (JRK), AD 0.002281 transcript variant 1 NM_016077.1 IOH3153 peptidyl-tRNA hydrolase 2 AD 0.002329 (PTRH2), nuclear gene encoding mitochondrial protein BC022362.1 IOH14191 cDNA clone MGC: 23888 Control 0.002364 IMAGE: 4704496, complete cds NM_014955.2 IOH45543 KIAA0859 (KIAA0859), AD 0.002364 transcript variant 2 NM_001834.2 IOH43456 clathrin, light chain (Lcb) (CLTB), Control 0.002495 transcript variant 1, mRNA. NM_002045.1 IOH6708 growth associated protein 43 Control 0.002495 (GAP43) NM_003503.2 Cell division cycle 7-related AD 0.00252 protein kinase NM_022491.2 IOH62643 Sin3 histone deacetylase Control 0.002538 corepressor complex component SDS3 NM_004987.3 IOH55033 LIM and senescent cell antigen- Control 0.002538 like-containing domain protein 1 BC017212.2 IOH13041 PHD finger protein 11 (PHF11) AD 0.0027 NM_019069.3 IOH26403 WD repeat domain 5B (WDR5B) AD 0.00274 BC094719.1 IOH62673 Rho GTPase-activating protein 12 AD 0.002753 BC021187.1 IOH10893 DKFZP434K028 protein AD 0.00278 (DKFZP434K028) NM_003948.2 Cyclin-dependent kinase-like 2 AD 0.00278 BC040183.2 IOH27627 Rap guanine nucleotide exchange AD 0.00278 factor (GEF) 4 (RAPGEF4) NM_014061.3 IOH10824 melanoma antigen family H, 1 AD 0.00278 (MAGEH1) BC032587.1 IOH21953 tubby like protein 3 (TULP3) AD 0.002953 BC005332.1 IOH7177 cDNA clone MGC: 12418 AD 0.003171 IMAGE: 3934658, complete cds BC033710.2 IOH45968 RAD54 homolog B (S. cerevisiae) AD 0.003171 (RAD54B) BC010425.1 IOH27813 acyl-Coenzyme A oxidase 1, AD 0.003171 palmitoyl (ACOX1) NM_021138.2 IOH21846 TNF receptor-associated factor 2 AD 0.003171 (TRAF2) BC093990.1 IOH62017 Sin3 histone deacetylase AD 0.003185 corepressor complex component SDS3 NM_014288.2 IOH13691 Centromere protein R AD 0.003283 NM_024826.1 IOH42194 Microtubule-associated protein 9 AD 0.003283 BC035968.1 IOH27970 chloride intracellular channel 5 AD 0.003283 (CLIC5) BC096165.1 IOH59027 Troponin I, cardiac muscle AD 0.003432 BC012105.1 IOH14609 nuclear VCP-like (NVL) AD 0.003548 BC011924.1 IOH12682 unkempt homolog (Drosophila)- AD 0.003548 like (UNKL) NM_001311.2 IOH5361 Cysteine-rich protein 1 AD 0.003548 NM_014445.2 IOH41298 stress-associated endoplasmic AD 0.003548 reticulum protein 1 (SERP1) NM_005979.1 IOH1589 S100 calcium binding protein A13 AD 0.003548 (S100A13), transcript variant 2 BC036923.1 IOH25928 chromosome 9 open reading frame AD 0.003733 150 (C9orf150) NM_033671.1 IOH43039 cyclin B3 (CCNB3), transcript AD 0.003733 variant 2 NM_201998.1 IOH56887 Splicing factor 1 Control 0.003827 BC014441.1 IOH13328 NOL1/NOP2/Sun domain family, AD 0.003841 member 4 (NSUN4) BC031549.1 IOH21007 CDC-like kinase 1 (CLK1) AD 0.003841 NM_194290.1 IOH42276 cDNA FLJ42001 fis, clone AD 0.003841 SPLEN2029912 (LOC153684 protein) [Source: UniProtKB/TrEMBL; Acc: Q6ZVW3] BC053984.1 IOH29361 immunoglobulin heavy variable 4- AD 0.003841 31 (IGHV4-31) BC050563.1 IOH26951 hypothetical protein LOC202051 AD 0.003841 (LOC202051) BC050718.1 IOH27017 polymerase (DNA directed) kappa AD 0.00385 (POLK) BC000896.1 IOH3226 RAB10, member RAS oncogene AD 0.00385 family (RAB10) NM_006252.2 IOH29876 AMP-activated protein_kinase AD 0.00385 A2/B1/G1: PRKAA2/B1/G1 sequences are seperated by -- (in protein list file). BC013630.1 IOH10193 JTV1 gene (JTV1) AD 0.00385 BC009108.1 IOH10191 cDNA clone IMAGE: 3451214 AD 0.003975 (MCM10) BC002645.1 IOH5243 syntaxin 5 (STX5) AD 0.003975 NM_138414.1 IOH10524 coiled-coil domain containing 101 AD 0.004133 (CCDC101) NM_002740.1 protein kinase C, iota (PRKCI) AD 0.004133 NM_002822.3 IOH40883 twinfilin, actin-binding protein, AD 0.004234 homolog 1 (Drosophila) (TWF1) BC003566.1 IOH4871 zinc finger protein 24 (ZNF24) AD 0.004412 NM_022756.2 IOH13235 Uncharacterized protein C1orf149 AD 0.004679 NM_153035.1 IOH27410 chromosome 1 open reading frame AD 0.004754 83 (C1orf83) NM_177524.1 IOH45900 mesoderm specific transcript AD 0.004766 homolog (mouse) (MEST), transcript variant 2 NM_004635.2 IOH3889 mitogen-activated protein kinase- AD 0.004766 activated protein kinase 3 (MAPKAPK3) NM_005607.1 Focal adhesion kinase 1 AD 0.004766 BC010697.1 IOH9799 RNA-binding protein 40 AD 0.004766 NM_174942.1 IOH26291 GAS2-like protein 3 AD 0.004766 BC038976.1 IOH28763 Rho GTPase-activating protein 15 AD 0.004867 NM_012117.1 IOH3162 chromobox homolog 5 (HP1 alpha AD 0.004867 homolog, Drosophila) (CBX5) NM_013313.3 IOH43282 yippee-like 1 (Drosophila) AD 0.005052 (YPEL1) NM_148179.1 IOH23094 chromosome 9 open reading frame AD 0.0051 23 (C9orf23), transcript variant 2 BC038105.2 IOH27173 membrane protein, palmitoylated AD 0.0051 7 (MAGUK p55 subfamily member 7) (MPP7) BC091489.1 IOH62570 zinc finger, MYND domain AD 0.0051 containing 11, mRNA (cDNA clone MGC: 111056 IMAGE: 6186814), complete cds BC034435.1 IOH21500 zinc finger CCCH-type containing AD 0.0051 3 (ZC3H3) NM_152736.2 IOH14153 Zinc finger protein 187 AD 0.0051 NM_015014.1 IOH23193 RNA binding motif protein 34 AD 0.005622 (RBM34) NM_003137.2 SFRS protein kinase 1 (SRPK1) AD 0.005622 BC016486.1 IOH21471 lectin, galactoside-binding, AD 0.005695 soluble, 8 (galectin 8) (LGALS8) BC000238.1 IOH4394 ankyrin repeat and zinc finger AD 0.005695 domain containing 1 (ANKZF1) NM_002904.4 IOH14621 RD RNA binding protein (RDBP) AD 0.005695 BC009046.1 IOH3394 neurogenic differentiation 1 AD 0.005695 (NEUROD1) NM_198965.1 IOH44500 Parathyroid hormone-related AD 0.005695 protein BC047776.2 IOH26688 coiled-coil domain containing 43 AD 0.005695 (CCDC43) BC002914.1 IOH5733 WAS/WASL-interacting protein Control 0.005832 family member 1 NM_001004306.1 IOH40085 similar to hypothetical protein AD 0.005898 FLJ36492 (MGC87631) NM_006800.2 IOH45528 male-specific lethal 3-like 1 AD 0.005898 (Drosophila) (MSL3L1), transcript variant 3 NM_006038.1 IOH14383 spermatogenesis associated 2 AD 0.005898 (SPATA2) NM_014477.2 IOH22106 chromosome 20 open reading AD 0.005898 frame 10 (C20orf10) BC027612.2 IOH11844 EP300-interacting inhibitor of AD 0.005898 differentiation 3 NM_017411.2 IOH10903 survival of motor neuron 2, AD 0.005898 centromeric (SMN2), transcript variant d BC004876.1 IOH5626 Protein MCM10 homolog AD 0.005898 NM_201516.1 IOH45833 H2A histone family, member V AD 0.005917 (H2AFV), transcript variant 4 NM_199290.2 IOH40757 Nascent polypeptide-associated Control 0.006165 complex subunit alpha-2 BC006273.1 IOH6379 T-cell activation NFKB-like Control 0.006165 protein (TA-NFKBH) NM_014012.2 IOH26198 RAS (RAD and GEM)-like GTP- Control 0.006165 binding 1 (REM1) BC012499.1 IOH11855 NAD-dependent deacetylase Control 0.006165 sirtuin-1 NM_022156.3 IOH39856 dihydrouridine synthase 1-like (S. cerevisiae) AD 0.006165 (DUS1L) BC015742.1 IOH12050 polymerase (DNA directed), eta AD 0.006497 (POLH) NM_001015509.1 IOH54713 Peptidyl-tRNA hydrolase 2, AD 0.006497 mitochondrial NM_014366.1 IOH4189 guanine nucleotide binding AD 0.006531 protein-like 3 (nucleolar) (GNL3), transcript variant 1 NM_018357.2 IOH6558 La ribonucleoprotein domain AD 0.006544 family, member 6 (LARP6), transcript variant 1 BC020221.1 IOH13291 SH3 and cysteine rich domain AD 0.006912 (STAC) NM_005307.1 G protein-coupled receptor kinase 4 AD 0.006912 NM_017785.2 IOH12118 coiled-coil domain containing 99 AD 0.006926 (CCDC99) BC026101.2 IOH10652 nudE nuclear distribution gene E AD 0.006926 homolog (A. nidulans)-like 1 (NDEL1) NM_175571.2 IOH44212 GTPase, IMAP family member 8 AD 0.006926 (GIMAP8) NM_004286.2 IOH14552 GTP binding protein 1 (GTPBP1) AD 0.006926 BC072461.1 IOH62565 Cysteine and histidine-rich AD 0.006926 domain-containing protein 1 BC047945.1 IOH26362 tripartite motif-containing 69 AD 0.006926 (TRIM69) BC005858.1 IOH5967 fibronectin 1 (FN1) AD 0.006926 NM_001722.2 IOH4103 polymerase (RNA) III (DNA AD 0.006926 directed) polypeptide D, 44 kDa (POLR3D) NM_024333.1 IOH4546 Fibronectin type III and SPRY AD 0.006926 domain-containing protein 1 NM_144595.1 IOH25832 SLAIN motif family, member 1 AD 0.006926 (SLAIN1), transcript variant 2 NM_002469.1 IOH13806 myogenic factor 6 (herculin) AD 0.006926 (MYF6) BC053866.1 IOH28947 endothelin 3 (EDN3) AD 0.006926 NM_001319.5 IOH10417 casein kinase 1, gamma 2 AD 0.006926 (CSNK1G2) BC006124.1 IOH6586 IMP (inosine monophosphate) AD 0.006926 dehydrogenase 2 (IMPDH2) NM_014667.1 IOH29305 vestigial like 4 (Drosophila) AD 0.006926 (VGLL4) NM_031465.2 IOH6623 chromosome 12 open reading AD 0.006926 frame 32 (C12orf32) NM_182612.1 IOH42453 Parkinson disease 7 domain AD 0.006926 containing 1 (PDDC1) PV4803 epidermal growth factor receptor AD 0.006926 (erythroblastic leukemia viral (v- erb-b) oncogene homolog, avian) (EGFR); see catalog number for detailed information on wild-type or point mutant status NM_152266.1 IOH13579 chromosome 19 open reading AD 0.006926 frame 40 (C19orf40) NM_000997.2 IOH1585 ribosomal protein L37 (RPL37) AD 0.00699 BC001728.1 IOH4430 TCF3 fusion partner AD 0.00699 BC007015.1 IOH29312 cyclin E2 (CCNE2) AD 0.00699 NM_022347.1 IOH41552 interferon responsive gene 15 AD 0.00699 (IFRG15) BC031821.1 IOH22188 Secernin-3 AD 0.007845 NM_016304.2 IOH7552 chromosome 15 open reading AD 0.007845 frame 15 (C15orf15) BC069677.1 IOH61907 Regulator of G-protein signaling 8 AD 0.008076 BC013331.1 IOH13858 H2A histone family, member Y AD 0.008076 (H2AFY) NM_017838.2 IOH4642 nucleolar protein family A, AD 0.008076 member 2 (H/ACA small nucleolar RNPs) (NOLA2), transcript variant 1 BC013796.1 IOH21478 adaptor-related protein complex 2, AD 0.008076 mu 1 subunit (AP2M1) NM_080743.2 IOH10836 serine-arginine repressor protein AD 0.008076 (35 kDa) (SRrp35) BC000190.1 IOH4410 zinc finger, C3HC-type containing AD 0.008141 1 (ZC3HC1) BC036089.1 IOH27267 myeloid/lymphoid or mixed- AD 0.008141 lineage leukemia (trithorax homolog, Drosophila); translocated to, 3 (MLLT3) NM_018215.2 IOH40888 hypothetical protein FLJ10781 AD 0.008141 (FLJ10781), transcript variant 1 BC095401.1 IOH62645 AKT-interacting protein AD 0.008141 BC006456.1 IOH5963 family with sequence similarity Control 0.008294 21, member C (FAM21C) BC033777.2 IOH21769 amyotrophic lateral sclerosis 2 Control 0.008368 (juvenile) chromosome region, candidate 8 (ALS2CR8) NM_001008572.1 IOH45757 tubulin tyrosine ligase-like family, AD 0.008509 member 1 (TTLL1), transcript variant 2 BC103812.1 IOH63363 Alpha-ketoglutarate-dependent AD 0.008559 dioxygenase alkB homolog 3 BC036365.1 IOH22309 PH domain-containing protein AD 0.008559 C10orf81 NM_024718.2 IOH40918 chromosome 9 open reading frame Control 0.009125 86 (C9orf86) BC013031.1 IOH13433 Pleckstrin homology-like domain Control 0.009125 family B member 1 NM_022110.2 IOH10458 FK506 binding protein like Control 0.009125 (FKBPL) NM_016047.1 IOH11089 splicing factor 3B, 14 kDa subunit AD 0.009549 (SF3B14) BC014949.1 IOH13331 DEXH (Asp-Glu-X-His) box AD 0.009549 polypeptide 58 (DHX58) BC047690.1 IOH28834 Ras-related protein M-Ras AD 0.009633 NM_001894.2 IOH21160 casein kinase 1, epsilon AD 0.009633 (CSNK1E), transcript variant 2 NM_006482.1 Dual specificity tyrosine- AD 0.009633 phosphorylation-regulated kinase 2 NM_025104.2 IOH59472 Protein DBF4 homolog B AD 0.009633 BC004410.1 IOH5586 Zinc finger protein castor homolog 1 Control 0.009819 NM_017819.1 IOH45746 RNA (guanine-9-)- AD 0.009872 methyltransferase domain- containing protein 1, mitochondrial BC029382.1 IOH23139 Angiogenic factor with G patch Control 0.010166 and FHA domains 1 NM_199139.1 IOH44783 XIAP associated factor-1 (XAF1), AD 0.010291 transcript variant 2 NM_003910.2 IOH23209 BUD31 homolog (S. cerevisiae) AD 0.010291 (BUD31) BC000442.1 Serine/threonine-protein kinase 12 AD 0.010291 BC028711.2 IOH11814 cancer/testis antigen CT45-3 AD 0.010291 (CT45-3) NM_018158.1 IOH38323 solute carrier family 4 (anion AD 0.010774 exchanger), member 1, adaptor protein (SLC4A1AP) BC034692.1 IOH22176 anillin, actin binding protein AD 0.010774 (ANLN) NM_173605.1 IOH21690 potassium channel regulator AD 0.010774 (KCNRG), transcript variant 1 NM_014047.1 IOH11187 chromosome 19 open reading AD 0.010774 frame 53 (C19orf53) BC073791.1 IOH63073 immunoglobulin kappa constant, AD 0.010774 mRNA (cDNA clone MGC: 88809 IMAGE: 6279986), complete cds BC014928.1 IOH10102 MYC-induced nuclear antigen AD 0.010774 BC053656.1 IOH28981 EGF-like repeats and discoidin I- AD 0.010774 like domains 3 (EDIL3) XM_378879.2 IOH42915 PREDICTED: Homo sapiens AD 0.010774 hypothetical LOC400763 (LOC400763) NM_017817.1 IOH12515 RAB20, member RAS oncogene AD 0.010774 family (RAB20) BC031608.1 IOH22796 REST corepressor 3 (RCOR3) AD 0.010774 BC047722.1 IOH26651 hypothetical protein MGC52110 AD 0.010774 (MGC52110) BC020726.1 IOH12969 sciellin (SCEL) AD 0.010774 NM_024039.1 IOH4379 MIS12, MIND kinetochore AD 0.010774 complex component, homolog (yeast) (MIS12) BC026213.1 IOH11042 F-box/WD repeat-containing AD 0.010774 protein 11 NM_002135.3 IOH10133 nuclear receptor subfamily 4, AD 0.010822 group A, member 1 (NR4A1), transcript variant 1 NM_015939.2 IOH3137 tRNA methyltransferase 6 AD 0.010846 homolog (S. cerevisiae) (TRMT6) NM_018039.2 IOH43857 jumonji domain containing 2D AD 0.010846 (JMJD2D) NM_007373.2 IOH26711 soc-2 suppressor of clear homolog AD 0.010846 (C. elegans) (SHOC2) BC022996.1 IOH10666 SH3 domain-binding protein 2 Control 0.011036 BC067120.1 IOH40451 protein tyrosine phosphatase AD 0.011036 domain containing 1, mRNA (cDNA clone MGC: 70358 IMAGE: 5539182), complete cds BC027729.1 IOH14530 tetra-peptide repeat homeobox- Control 0.01201 like (TPRXL) BC054520.1 IOH28900 myocyte enhancer factor 2D Control 0.01201 (MEF2D) NM_015918.2 IOH10987 processing of precursor 5, AD 0.012016 ribonuclease P/MRP subunit (S. cerevisiae) (POP5), transcript variant 1 NM_152677.1 IOH34851 zinc finger and SCAN domain AD 0.012016 containing 4 (ZSCAN4) BC008902.2 IOH7022 GRIP and coiled-coil domain- AD 0.012016 containing protein 1 NM_001008239.1 IOH45708 chromosome 18 open reading AD 0.012016 frame 25 (C18orf25), transcript variant 2 NM_183397.1 IOH44678 peroxisomal membrane protein 4, AD 0.012016 24 kDa (PXMP4), transcript variant 2 NM_006337.3 IOH12378 microspherule protein 1 (MCRS1), AD 0.012016 transcript variant 1 NM_203305.1 IOH26383 family with sequence similarity Control 0.012091 102, member A (FAM102A), transcript variant 2 BC034401.1 IOH22782 cDNA clone IMAGE: 5172086, AD 0.012151 partial cds NM_006755.1 IOH2052 transaldolase 1 (TALDO1) AD 0.012151 NM_004853.1 IOH9940 syntaxin 8 (STX8) AD 0.012151 BC036910.1 IOH25910 hypothetical LOC388882 AD 0.012151 (LOC388882) BC094687.1 IOH62581 Elongation factor 1-alpha 1 AD 0.012151 BC011713.2 IOH22973 tRNA methyltransferase 12 Control 0.013018 homolog (S. cerevisiae) (TRMT12) NM_006263.1 IOH3647 proteasome (prosome, macropain) Control 0.013018 activator subunit 1 (PA28 alpha) (PSME1), transcript variant 1 NM_144608.1 IOH14178 hexamthylene bis-acetamide AD 0.013303 inducible 2 (HEXIM2) NM_024038.2 IOH5926 chromosome 19 open reading Control 0.013303 frame 43 (C19orf43) NM_003831.1 IOH20968 RIO kinase 3 (yeast) (RIOK3) AD 0.013332 BC020555.1 IOH10305 SERPINE1 mRNA binding Control 0.013333 protein 1 (SERBP1) BC009250.1 IOH27775 guanine nucleotide binding AD 0.013333 protein-like 2 (nucleolar) (GNL2) BC032598.1 IOH21976 NHL repeat containing 2 AD 0.013369 (NHLRC2) NM_018697.3 IOH37734 LanC lantibiotic synthetase AD 0.013369 component C-like 2 (bacterial) (LANCL2) NM_024104.1 IOH3754 chromosome 19 open reading AD 0.013369 frame 42 (C19orf42) BC030665.1 IOH22451 Sulfotransferase 4A1 AD 0.013369 BC004955.1 IOH5528 ATPase inhibitory factor 1 AD 0.013369 (ATPIF1) BC009010.1 IOH3292 Uncharacterized protein C6orf142 AD 0.013369 homolog BC012887.1 IOH25768 Nucleolar and spindle-associated AD 0.013369 protein 1 BC015066.1 IOH13784 core-binding factor, runt domain, AD 0.013369 alpha subunit 2; translocated to, 2 (CBFA2T2) BC052303.1 IOH28113 Rho GTPase activating protein 4 AD 0.013369 (ARHGAP4) NM_080414.1 IOH42243 vacuolar protein sorting 16 AD 0.013369 homolog (S. cerevisiae) (VPS16), transcript variant 2 NM_001790.2 IOH14569 cell division cycle 25 homolog C AD 0.013369 (S. pombe) (CDC25C), transcript variant 1 PHC0045 interleukin 4 (IL4), transcript AD 0.013369 variant 1 NM_145041.1 IOH13199 transmembrane protein 106A AD 0.013369 (TMEM106A) NM_021639.2 IOH10045 GC-rich promoter binding protein AD 0.013369 1-like 1 (GPBP1L1) BC028295.1 IOH25815 peptidase D (PEPD) AD 0.013369 PV3612 aurora kinase A (AURKA), AD 0.013369 transcript variant 2 NM_032321.1 IOH6608 hypothetical protein MGC13057 AD 0.013369 (MGC13057), transcript variant 4 BC010033.1 IOH27835 quinolinate AD 0.013369 phosphoribosyltransferase (nicotinate-nucleotide pyrophosphorylase (carboxylating)) (QPRT) NM_001064.1 IOH61026 Transketolase AD 0.013369 NM_017572.2 IOH53775 MAP kinase-interacting AD 0.013967 serine/threonine-protein kinase 2 NM_022650.1 IOH41794 RAS p21 protein activator AD 0.013967 (GTPase activating protein) 1 (RASA1), transcript variant 2 NM_020781.2 IOH45442 zinc finger protein 398 (ZNF398), AD 0.013967 transcript variant 2 NM_182597.1 IOH44503 Coiled-coil domain-containing Control 0.014519 transmembrane protein C7orf53 NM_001008211.1 IOH57143 Optineurin Control 0.014972 NM_006246.2 IOH29856 protein phosphatase 2, regulatory Control 0.014972 subunit B′, epsilon isoform (PPP2R5E) NM_148912.2 IOH40097 abhydrolase domain containing 11 Control 0.014972 (ABHD11) BC053617.1 IOH29004 B-cell CLL/lymphoma 10 Control 0.014972 (BCL10) NM_021643.1 IOH21149 tribbles homolog 2 (Drosophila) Control 0.014972 (TRIB2) NM_024313.1 IOH5392 nucleolar protein 12 (NOL12) Control 0.014972 NM_002735.1 IOH42254 cAMP-dependent protein kinase Control 0.014972 type I-beta regulatory subunit NM_032929.1 IOH7540 ubiquitin specific protease 45 Control 0.014972 (USP45) NM_024692.3 IOH42634 CAP-GLY domain containing Control 0.015635 linker protein family, member 4 (CLIP4) NM_002391.1 IOH13794 midkine (neurite growth- AD 0.015891 promoting factor 2) (MDK), transcript variant 3 NM_006298.2 IOH34757 zinc finger protein 192 (ZNF192) AD 0.015891 BC047536.1 IOH27737 sciellin (SCEL) AD 0.015891 NM_139062.1 IOH23025 casein kinase 1, delta (CSNK1D), AD 0.015891 transcript variant 2 NM_005639.1 IOH29114 synaptotagmin I (SYT1) AD 0.015891 BC006811.1 IOH3174 peroxisome proliferator-activated AD 0.015961 receptor gamma (PPARG) BC008364.1 IOH5969 heterogeneous nuclear AD 0.015961 ribonucleoprotein C (C1/C2) (HNRPC) NM_032345.1 IOH6625 within bgcn homolog (Drosophila) AD 0.015961 (WIBG) BC040949.1 IOH26268 myocyte enhancer factor 2D Control 0.016176 (MEF2D) NM_005522.3 IOH21992 homeobox A1 (HOXA1), Control 0.016176 transcript variant 1 BC016825.1 IOH14707 spire homolog 1 (Drosophila) AD 0.016623 (SPIRE1) NM_020664.3 IOH9825 2,4-dienoyl CoA reductase 2, AD 0.017399 peroxisomal (DECR2) NM_173547.2 IOH11612 tripartite motif-containing 65 Control 0.017399 (TRIM65) NM_017542.3 IOH43680 pogo transposable element with AD 0.017399 KRAB domain (POGK) NM_003160.1 Serine/threonine-protein kinase 13 AD 0.017399 NM_032550.1 IOH10814 actin filament associated protein Control 0.017478 1-like 2 (AFAP1L2), transcript variant 2 NM_004527.2 IOH40231 mesenchyme homeobox 1 Control 0.017478 (MEOX1), transcript variant 1 BC031687.1 IOH21501 drebrin-like (DBNL) Control 0.017478 BC026346.1 IOH10816 family with sequence similarity AD 0.017478 84, member A (FAM84A) BC041037.1 IOH28003 immunoglobulin heavy constant AD 0.017478 mu (IGHM) BC028039.1 IOH11511 hypothetical protein MGC39900 Control 0.01748 (MGC39900) BC033677.1 IOH40219 Uncharacterized protein C9orf114 AD 0.017534 BC064145.1 IOH40031 CDK5 regulatory subunit AD 0.017664 associated protein 1-like 1 (CDKAL1) NM_138565.1 IOH6227 cortactin (CTTN), transcript AD 0.017664 variant 2 NM_018441.2 IOH4050 peroxisomal trans-2-enoyl-CoA Control 0.018299 reductase (PECR) NM_022823.1 IOH21980 fibronectin type III domain AD 0.018299 containing 4 (FNDC4) NM_015871.2 IOH4113 zinc finger protein 593 (ZNF593) Control 0.01832 NM_024096.1 IOH3203 XTP3-transactivated protein A Control 0.01863 (XTP3TPA) BC023546.2 IOH29323 LIM and calponin homology Control 0.018757 domains 1 (LIMCH1) NM_015621.2 IOH43603 coiled-coil domain containing 69 Control 0.018757 (CCDC69) BC006104.1 IOH6588 RIO kinase 1 (yeast) (RIOK1) AD 0.018757 BC014975.1 IOH14285 family with sequence similarity AD 0.018844 136, member A (FAM136A) NM_138730.1 IOH9857 high mobility group nucleosomal AD 0.018844 binding domain 3 (HMGN3), transcript variant 2 BC000226.1 IOH4362 ubiquitin specific peptidase 47 Control 0.019006 (USP47) NM_007242.3 IOH3925 DEAD (Asp-Glu-Ala-As) box Control 0.019006 polypeptide 19B (DDX19B), transcript variant 1 NM_025004.1 IOH43200 Coiled-coil domain-containing AD 0.019314 protein 15 NM_004092.2 IOH54943 Enoyl-CoA hydratase, AD 0.019314 mitochondrial NM_021107.1 IOH6073 mitochondrial ribosomal protein AD 0.019314 S12 (MRPS12), nuclear gene encoding mitochondrial protein, transcript variant 1 NM_053049.2 IOH54667 Urocortin-3 AD 0.019314 NM_001545.1 IOH11951 immature colon carcinoma AD 0.019314 transcript 1 (ICT1) NM_148571.1 IOH41376 mitochondrial ribosomal protein AD 0.019314 L27 (MRPL27), nuclear gene encoding mitochondrial protein, transcript variant 2 NM_001003799.1 IOH45702 TCR gamma alternate reading AD 0.019314 frame protein (TARP), nuclear gene encoding mitochondrial protein, transcript variant 1 BC017227.1 IOH12094 phosducin-like (PDCL) AD 0.019314 NM_172159.2 IOH25842 potassium voltage-gated channel, AD 0.019314 shaker-related subfamily, beta member 1 (KCNAB1), transcript variant 3 NM_000462.2 IOH38426 ubiquitin protein ligase E3A AD 0.019314 (human papilloma virus E6- associated protein, Angelman syndrome) (UBE3A), transcript variant 2 XM_210860.4 IOH44696 PREDICTED: Homo sapiens AD 0.019314 hypothetical LOC283034 (LOC283034) BC022344.1 IOH14799 twinfilin, actin-binding protein, AD 0.019314 homolog 1 (Drosophila) (TWF1) NM_005037.3 IOH39661 peroxisome proliferator-activated AD 0.019314 receptor gamma (PPARG), transcript variant 4 NM_022977.1 IOH42656 acyl-CoA synthetase long-chain AD 0.019314 family member 4 (ACSL4), transcript variant 2 NM_006217.2 IOH11838 serpin peptidase inhibitor, clade I AD 0.019314 (pancpin), member 2 (SERPINI2) NM_024979.2 IOH23111 Guanine nucleotide exchange AD 0.019314 factor DBS NM_016286.1 IOH4017 dicarbonyl/L-xylulose reductase AD 0.019314 (DCXR) NM_003160.1 Serine/threonine-protein kinase 13 AD 0.019314 NM_015687.2 IOH38763 filamin A interacting protein 1 AD 0.019314 (FILIP1) BC005871.2 IOH46098 chromosome 10 open reading AD 0.019314 frame 58 (C10orf58) NM_016216.2 IOH57112 Lariat debranching enzyme AD 0.019314 NM_017856.1 IOH3877 gem (nuclear organelle) associated AD 0.019314 protein 8 (GEMIN8), transcript variant 3 NM_015869.2 IOH36704 peroxisome proliferator-activated AD 0.019314 receptor gamma (PPARG), transcript variant 2 NM_001003397.1 IOH58745 Tumor protein D53 AD 0.019314 NM_001018061.1 IOH57329 UPF0544 protein C5orf45 AD 0.019314 [Source: UniProtKB/Swiss- Prot; Acc: Q6NTE8] NM_173060.1 IOH52621 Calpastatin Control 0.019703 BC013900.1 IOH27818 chromosome 12 open reading AD 0.020182 frame 41 (C12orf41) BC022988.1 IOH22366 chromosome 6 open reading frame AD 0.020182 65 (C6orf65) NM_006299.2 IOH12838 zinc finger protein 193 (ZNF193) AD 0.020182 BC018847.1 IOH14862 Transaldolase AD 0.020182 BC052805.1 IOH29378 erythrocyte membrane protein Control 0.020182 band 4.9 (dematin) (EPB49) NM_139355.1 IOH4506 megakaryocyte-associated tyrosine AD 0.0209 kinase (MATK), transcript variant 1 NM_207356.1 IOH40044 chromosome 1 open reading frame AD 0.0209 174 (C1orf174) NM_001008737.1 IOH42047 hypothetical LOC401052 AD 0.0209 (LOC401052) NM_145109.1 IOH21715 mitogen-activated protein kinase AD 0.0209 kinase 3 (MAP2K3), transcript variant B BC017114.1 IOH9995 oligonucleotide/oligosaccharide- AD 0.0209 binding fold containing 2A (OBFC2A) XM_086879.4 IOH43381 PREDICTED: Homo sapiens AD 0.0209 hypothetical LOC150371 (LOC150371) NM_078630.1 IOH37755 male-specific lethal 3-like 1 AD 0.0209 (Drosophila) (MSL3L1), transcript variant 2 NM_005197.2 IOH56874 Forkhead box protein N3 AD 0.0209 NM_004602.2 IOH62672 Double-stranded RNA-binding AD 0.021101 protein Staufen homolog 1 BC017504.1 IOH12256 Differentially expressed in FDCP AD 0.021101 6 homolog NM_014763.2 IOH23003 mitochondrial ribosomal protein Control 0.021448 L19 (MRPL19), nuclear gene encoding mitochondrial protein NM_003590.2 IOH26262 cullin 3 (CUL3) AD 0.021703 NM_145702.1 IOH40861 tigger transposable element AD 0.021703 derived 1 (TIGD1) BC001935.1 IOH5068 cyclin-dependent kinase inhibitor AD 0.022172 1A (p21, Cip1) (CDKN1A) NM_031472.1 IOH5640 tRNA phosphotransferase 1 Control 0.023801 (TRPT1), transcript variant 2 NM_032141.1 IOH43707 coiled-coil domain containing 55 Control 0.024725 (CCDC55), transcript variant 1 NM_004965.3 IOH4772 high-mobility group nucleosome AD 0.024725 binding domain 1 (HMGN1) BC032508.1 IOH62199 PNMA-like 1, mRNA (cDNA AD 0.025032 clone MGC: 45422 IMAGE: 5246377), complete cds BC013966.2 IOH12372 family with sequence similarity AD 0.025523 64, member A (FAM64A) NM_020236.2 IOH13751 mitochondrial ribosomal protein AD 0.025523 L1 (MRPL1), nuclear gene encoding mitochondrial protein BC043247.2 IOH28730 transducin-like enhancer of split 3 AD 0.025523 (E(sp1) homolog, Drosophila) (TLE3) BC057806.1 IOH29150 insulin-like growth factor binding AD 0.025523 protein 1 (IGFBP1) NM_006573.2 IOH12947 tumor necrosis factor (ligand) AD 0.025523 superfamily, member 13b (TNFSF13B) BC025406.1 IOH11226 phosphodiesterase 4D interacting AD 0.025523 protein (myomegalin) (PDE4DIP) BC002559.1 IOH4053 YTH domain family, member 2 AD 0.025523 (YTHDF2) NM_052926.1 IOH35779 Paraneoplastic antigen-like protein 5 AD 0.025523 NM_006254.3 IOH26352 protein kinase C, delta (PRKCD), AD 0.025523 transcript variant 1 BC022003.1 IOH11205 myotubularin related protein 9 AD 0.025523 (MTMR9) BC043348.2 IOH26348 retinitis pigmentosa 2 (X-linked AD 0.025523 recessive) (RP2) NM_018010.2 IOH12676 intraflagellar transport 57 homolog AD 0.025523 (Chlamydomonas) (IFT57) BC044851.1 IOH27643 vacuolar protein sorting 41 AD 0.025523 homolog (S. cerevisiae) (VPS41) BC068094.1 IOH40788 SH3 domain and tetratricopeptide AD 0.025523 repeats 1 (SH3TC1) NM_020961.2 IOH6104 KIAA1627 protein (KIAA1627) AD 0.025523 PV3757 myosin light chain kinase 2, AD 0.025523 skeletal muscle (MYLK2) NM_002451.3 IOH54928 methylthioadenosine AD 0.025523 phosphorylase (MTAP), mRNA. NM_000281.1 IOH6468 pterin-4 alpha-carbinolamine AD 0.025523 dehydratase/dimerization cofactor of hepatocyte nuclear factor 1 alpha (TCF1) (PCBD1) NM_144982.1 IOH12275 coiled-coil domain containing 131 AD 0.025523 (CCDC131) NM_017927.2 IOH43690 mitofusin 1 (MFN1), nuclear gene AD 0.025523 encoding mitochondrial protein, transcript variant 2 NM_002150.1 IOH14718 4-hydroxyphenylpyruvate AD 0.025523 dioxygenase NM_016267.1 IOH2890 vestigial like 1 (Drosophila) AD 0.025523 (VGLL1) BC067299.1 IOH40040 Mdm4, transformed 3T3 cell AD 0.025523 double minute 4, p53 binding protein (mouse) (MDM4) XM_378988.2 IOH41598 PREDICTED: Homo sapiens AD 0.025523 hypothetical LOC400849 (LOC400849) NM_006466.1 IOH14273 polymerase (RNA) III (DNA AD 0.025523 directed) polypeptide F, 39 kDa (POLR3F) BC042608.1 IOH27462 family with sequence similarity AD 0.025523 90, member A1 (FAM90A1) NM_025136.1 IOH6524 optic atrophy 3 (autosomal AD 0.025523 recessive, with chorea and spastic paraplegia) (OPA3), transcript variant 2 BC012620.1 IOH12299 golgi SNAP receptor complex AD 0.025523 member 1 (GOSR1) NM_139244.2 IOH44877 syntaxin binding protein 5 AD 0.025523 (tomosyn) (STXBP5) NM_015929.2 IOH7138 lipoyltransferase 1 (LIPT1), AD 0.025523 transcript variant 1 PV3366 v-erb-b2 erythroblastic leukemia AD 0.025523 viral oncogene homolog 2, neuro/glioblastoma derived oncogene homolog (avian) (ERBB2), transcript variant 2 NM_133629.1 IOH43384 RAD51-like 3 (S. cerevisiae) AD 0.025523 (RAD51L3), transcript variant 4 XM_294794.1 IOH42923 PREDICTED: Homo sapiens AD 0.025523 similar to putative membrane- bound dipeptidase 2 (LOC339065) BC012289.1 IOH11447 KIAA0515 (KIAA0515) AD 0.025523 BC029444.1 IOH23178 immunoglobulin kappa constant AD 0.025523 (IGKC) BC015109.1 IOH14036 39S ribosomal protein L1, AD 0.025523 mitochondrial NM_024578.1 IOH23128 occludin/ELL domain containing 1 AD 0.025523 (OCEL1) NM_003908.1 IOH3554 eukaryotic translation initiation AD 0.025523 factor 2, subunit 2 beta, 38 kDa (EIF2S2) BC001726.1 IOH4820 Nucleolar protein 11 AD 0.025523 BC003666.2 IOH6106 NAD synthetase 1 (NADSYN1) AD 0.025523 NM_198491.1 IOH41015 family with sequence similarity AD 0.025523 92, member B (FAM92B) PV3817 WEE1 homolog (S. pombe) AD 0.025523 (WEE1) BC000974.2 IOH3026 WDR45-like (WDR45L) AD 0.025523 BC053675.1 IOH29030 thymopoietin (TMPO) AD 0.025523 BC033292.1 IOH26782 interleukin 20 receptor beta AD 0.025523 (IL20RB) BC002509.1 IOH3968 PHD finger protein 23 AD 0.025523 BC006969.1 IOH7343 dynein, cytoplasmic 2, light AD 0.025523 intermediate chain 1, mRNA (cDNA clone MGC: 12166 IMAGE: 3828551), complete cds BC069491.1 IOH40249 Cerberus AD 0.025523 NM_138559.1 IOH43559 B-cell CLL/lymphoma 11A (zinc AD 0.025523 finger protein) (BCL11A), transcript variant 3 BC004376.1 IOH5584 annexin A8 (ANXA8L1) AD 0.025523 NM_005620.1 IOH4079 S100 calcium binding protein A11 AD 0.025523 (S100A11) PV3872 epidermal growth factor receptor AD 0.025523 (erythroblastic leukemia viral (v- erb-b) oncogene homolog, avian) (EGFR); see catalog number for detailed information on wild-type or point mutant status NM_032214.1 IOH26309 Src-like-adaptor 2 (SLA2), AD 0.025523 transcript variant 1 NM_002444.1 IOH2457 moesin (MSN) AD 0.025523 NM_173796.2 IOH23049 hypothetical protein MGC24125 AD 0.025523 (MGC24125) NM_002648.1 pim-1 oncogene (PIM1) AD 0.025523 NM_001876.2 IOH52786 Carnitine O-palmitoyltransferase AD 0.025523 1, liver isoform BC014532.1 IOH12798 decapping enzyme, scavenger AD 0.025523 (DCPS) NM_001005266.1 IOH59477 Dresden prostate carcinoma AD 0.025523 protein 2 NM_007172.2 IOH40805 nucleoporin 50 kDa (NUP50), AD 0.025523 transcript variant 2 NM_018326.1 IOH14251 GTPase, IMAP family member 4 AD 0.025523 (GIMAP4) BC033881.1 IOH22099 XRCC6 binding protein 1 AD 0.025523 (XRCC6BP1) NM_020168.3 IOH20961 p21(CDKN1A)-activated kinase 6 AD 0.025523 (PAK6) NM_014790.3 IOH14698 janus kinase and microtubule AD 0.025562 interacting protein 2 (JAKMIP2) NM_032360.1 IOH6003 acyl-Coenzyme A binding domain AD 0.025562 containing 6 (ACBD6) NM_006303.2 IOH5395 JTV1 gene (JTV1) AD 0.025562 BC017305.1 IOH12450 sirtuin (silent mating type AD 0.025562 information regulation 2 homolog) 7 (S. cerevisiae) (SIRT7) BC051762.1 IOH28838 Uncharacterized protein C20orf96 AD 0.025562 NM_145010.1 IOH10871 chromosome 10 open reading AD 0.025589 frame 63 (C10orf63) NM_206834.1 IOH40081 Uncharacterized protein C6orf201 AD 0.027186 BC009350.1 IOH14087 Eukaryotic translation initiation AD 0.027186 factor 2-alpha kinase 4 NM_003720.1 IOH3819 Proteasome assembly chaperone 1 AD 0.027186 NM_001906.1 IOH7194 chymotrypsinogen B1 (CTRB1) Control 0.027437 BC037900.2 IOH27758 C-terminal binding protein 2 Control 0.027437 (CTBP2) NM_138960.3 IOH59763 Homeobox protein TGIF2LX Control 0.027437 BC067755.1 IOH40120 potassium channel tetramerisation AD 0.027437 domain containing 18 (KCTD18) BC005840.2 IOH46093 selenoprotein S (SELS) AD 0.027437 BC000934.2 IOH2996 eukaryotic translation initiation AD 0.027601 factor 2, subunit 2 beta, 38 kDa (EIF2S2) BC038838.1 IOH28760 Proline-rich protein 16 Control 0.027601 NM_020175.1 IOH13452 dihydrouridine synthase 3-like (S. cerevisiae) AD 0.027808 (DUS3L) BC002695.1 IOH5262 AP2 associated kinase 1 (AAK1) Control 0.028183 NM_032472.3 IOH44558 Peptidyl-prolyl cis-trans Control 0.028183 isomerase-like 3 NM_016185.1 IOH4078 hematological and neurological Control 0.028183 expressed 1 (HN1), transcript variant 1 BC032372.1 IOH21643 Ral GEF with PH domain and Control 0.028183 SH3 binding motif 1 (RALGPS1) NM_002994.2 IOH7295 chemokine (C—X—C motif) ligand 5 Control 0.028183 (CXCL5) NM_176783.1 IOH40962 proteasome (prosome, macropain) Control 0.028183 activator subunit 1 (PA28 alpha) (PSME1), transcript variant 2 BC053872.1 IOH28961 copine V (CPNE5) Control 0.028183 BC017236.1 IOH14401 Casein kinase I isoform gamma-1 Control 0.028183 BC014667.1 IOH14303 immunoglobulin heavy constant AD 0.028183 gamma 1 (G1m marker) (IGHG1) NM_201403.1 IOH42184 MOB1, Mps One Binder kinase AD 0.028996 activator-like 2C (yeast) (MOBKL2C), transcript variant 2 NM_006640.2 IOH12164 septin 9 (SEPT9) Control 0.028996 BC010537.1 IOH10170 SUB1 homolog (S. cerevisiae) AD 0.029607 (SUB1) NM_170746.2 IOH58679 Selenoprotein H AD 0.029607 NM_031296.1 IOH43454 RAB33B, member RAS oncogene Control 0.030052 family (RAB33B) NM_032459.1 IOH21413 embryonal Fyn-associated Control 0.030431 substrate (EFS), transcript variant 2 NM_003092.3 IOH21977 small nuclear ribonucleoprotein AD 0.030431 polypeptide B″ (SNRPB2), transcript variant 1 NM_005105.2 IOH10383 RNA binding motif protein 8A AD 0.030921 (RBM8A) BC022571.1 IOH22219 prune homolog 2 (Drosophila) Control 0.031626 (PRUNE2) NM_002714.2 IOH39632 protein phosphatase 1, regulatory Control 0.031794 (inhibitor) subunit 10 (PPP1R10) NM_153450.1 IOH27352 mediator complex subunit 19 Control 0.031794 (MED19) BC104468.1 IOH63630 Outer dense fiber protein 3-like Control 0.031794 protein 2 BC047411.1 IOH26516 tubulin tyrosine ligase-like family, AD 0.031794 member 2 (TTLL2) NM_199188.1 IOH38224 La ribonucleoprotein domain AD 0.031794 family, member 4 (LARP4), transcript variant 2 BC003551.1 IOH4964 transglutaminase 2 (C polypeptide, AD 0.032518 protein-glutamine-gamma- glutamyltransferase) (TGM2) BC020647.1 IOH12765 coiled-coil domain containing 59 AD 0.032518 (CCDC59) BC048301.1 IOH26612 zinc finger, CCHC domain Control 0.032529 containing 11 (ZCCHC11) BC011781.2 IOH13131 chromosome 9 open reading frame AD 0.032529 37 (C9orf37) NM_001033551.1 IOH26533 TOM1-like protein 2 Control 0.032802 NM_177973.1 IOH22150 sulfotransferase family, cytosolic, Control 0.032802 2B, member 1 (SULT2B1), transcript variant 2 NM_006907.2 IOH59071 Pyrroline-5-carboxylate reductase Control 0.032802 1, mitochondrial NM_032858.1 IOH12001 maelstrom homolog (Drosophila) AD 0.033103 (MAEL) NM_144971.1 IOH10719 hypothetical protein MGC26641 AD 0.033103 (MGC26641) BC017440.1 IOH14659 trafficking protein particle AD 0.033103 complex 2-like (TRAPPC2L) BC017018.1 IOH11265 DnaJ (Hsp40) homolog, subfamily AD 0.033103 C, member 12 (DNAJC12) NM_144767.3 IOH44040 A kinase (PRKA) anchor protein AD 0.033103 13 (AKAP13), transcript variant 3 NM_018297.2 IOH6809 N-glycanase 1 (NGLY1) AD 0.033103 NM_031845.1 IOH37776 microtubule-associated protein 2 Control 0.033103 (MAP2), transcript variant 2 NM_002307.1 IOH40009 lectin, galactoside-binding, AD 0.03362 soluble, 7 (galectin 7) (LGALS7) NM_003939.2 IOH42069 beta-transducin repeat containing AD 0.03362 (BTRC), transcript variant 2, mRNA. NM_013242.1 IOH5166 chromosome 16 open reading AD 0.03362 frame 80 (C16orf80) NM_152285.1 IOH21698 arrestin domain containing 1 AD 0.033955 (ARRDC1) NM_178425.1 IOH38634 histone deacetylase 9 (HDAC9), AD 0.033955 transcript variant 5 NM_007255.1 IOH5828 xylosylprotein beta 1,4- AD 0.033955 galactosyltransferase, polypeptide 7 (galactosyltransferase I) (B4GALT7) NM_205833.1 IOH41224 immunoglobulin superfamily, AD 0.033955 member 1 (IGSF1), transcript variant 2 BC040457.1 IOH26807 calcium/calmodulin-dependent AD 0.033955 protein kinase (CaM kinase) II alpha (CAMK2A) NM_004732.1 IOH29581 potassium voltage-gated channel, AD 0.033955 shaker-related subfamily, beta member 3 (KCNAB3) NM_004450.1 IOH14288 enhancer of rudimentary homolog AD 0.033955 (Drosophila) (ERH) XM_378582.2 IOH43485 PREDICTED: Homo sapiens AD 0.033955 hypothetical LOC400523 (LOC400523) NM_001006666.1 IOH58588 apolipoprotein B mRNA editing AD 0.033955 enzyme, catalytic polypeptide-like 3F (APOBEC3F), transcript variant 2, mRNA. BC041876.1 IOH27738 tau tubulin kinase 2 (TTBK2) AD 0.033955 BC036335.1 IOH25781 BTB (POZ) domain containing 12 AD 0.033955 (BTBD12) BC036099.1 IOH27225 aryl-hydrocarbon receptor nuclear AD 0.033955 translocator 2 (ARNT2) NM_054012.1 IOH14007 argininosuccinate synthetase 1 AD 0.033955 (ASS1), transcript variant 2 NM_057749.1 IOH43526 cyclin E2 (CCNE2) AD 0.033955 PV3839 CDC-like kinase 4 (CLK4) AD 0.033955 BC005026.1 IOH6532 sirtuin (silent mating type AD 0.033955 information regulation 2 homolog) 6 (S. cerevisiae) (SIRT6) NM_013975.1 IOH40893 ligase III, DNA, ATP-dependent AD 0.033955 (LIG3), nuclear gene encoding mitochondrial protein, transcript variant alpha NM_181509.1 IOH42908 microtubule-associated protein 1 AD 0.033955 light chain 3 alpha (MAP1LC3A), transcript variant 2 BC001709.1 IOH4911 NAD kinase (NADK) AD 0.033955 NM_002638.1 IOH13658 peptidase inhibitor 3, skin-derived AD 0.033955 (SKALP) (PI3) NM_005901.2 IOH22138 SMAD family member 2 AD 0.033955 (SMAD2), transcript variant 1 BC046199.1 IOH26969 family with sequence similarity AD 0.033955 72, member B (FAM72B) NM_015417.2 IOH11253 sperm flagellar 1 (SPEF1) AD 0.033955 NM_018328.1 IOH12893 methyl-CpG binding domain AD 0.033955 protein 5 (MBD5) BC017328.2 IOH14721 angiotensin II receptor-associated AD 0.033955 protein (AGTRAP) NM_182739.1 IOH44393 NADH dehydrogenase AD 0.033955 (ubiquinone) 1 beta subcomplex, 6, 17 kDa (NDUFB6), nuclear gene encoding mitochondrial protein, transcript variant 2 NM_001032293.1 IOH3584 zinc finger protein 207 (ZNF207), AD 0.033955 transcript variant 2 NM_012227.1 IOH57121 Putative GTP-binding protein 6 AD 0.033955 BC026039.1 IOH40656 mitochondrial GTPase 1 homolog AD 0.033955 (S. cerevisiae) (MTG1) BC072409.1 IOH62546 Serine/threonine-protein AD 0.033955 phosphatase 4 regulatory subunit 3A BC066938.1 IOH40083 DEAD (Asp-Glu-Ala-Asp) box AD 0.034253 polypeptide 43 (DDX43) BC000712.1 IOH4703 kinesin family member C1 AD 0.034253 (KIFC1) BC000052.1 IOH4650 peroxisome proliferator-activated AD 0.035152 receptor alpha (PPARA) NM_199124.1 IOH43439 chromosome 11 open reading Control 0.035152 frame 63 (C11orf63), transcript variant 2 NM_004117.2 IOH27424 FK506 binding protein 5 (FKBP5) AD 0.035152 NM_002629.2 IOH13682 phosphoglycerate mutase 1 (brain) AD 0.035152 (PGAM1) NM_015122.1 IOH26137 FCH domain only 1 (FCHO1) AD 0.035152 NM_001021.2 IOH27847 ribosomal protein S17 (RPS17) AD 0.035152 NM_013323.1 IOH3822 sorting nexin 11 (SNX11), AD 0.035152 transcript variant 2 BC002950.1 IOH46164 chromosome 18 open reading AD 0.035152 frame 8 (C18orf8) NM_017612.1 IOH11180 Zinc finger CCHC domain- AD 0.035152 containing protein 8 BC035048.2 IOH27687 neurogenic differentiation 6 AD 0.035152 (NEUROD6) BC046117.1 IOH26985 dynein, axonemal, light AD 0.035152 intermediate chain 1 (DNALI1) NM_005335.3 IOH57089 Hematopoietic lineage cell- AD 0.035152 specific protein NM_144679.1 IOH40679 chromosome 17 open reading AD 0.035152 frame 56 (C17orf56) NM_004881.1 IOH3658 tumor protein p53 inducible AD 0.035152 protein 3 (TP53I3), transcript variant 1 NM_006442.2 IOH14520 DR1-associated protein 1 Control 0.035766 (negative cofactor 2 alpha) (DRAP1) BC047733.1 IOH26736 tRNA aspartic acid Control 0.035766 methyltransferase 1 (TRDMT1) NM_033122.1 IOH26918 chromosome 4 open reading frame Control 0.035766 35 (C4orf35) NM_080423.1 IOH23012 protein tyrosine phosphatase, non- Control 0.035766 receptor type 2 (PTPN2), transcript variant 3 BC015665.2 IOH40642 LATS, large tumor suppressor, Control 0.035766 homolog 1 (Drosophila) (LATS1) BC001716.1 IOH4447 poly(A) binding protein Control 0.035766 interacting protein 2 (PAIP2) NM_138316.2 IOH59336 Pantothenate kinase 1 Control 0.035766 NM_005900.1 IOH4970 SMAD family member 1 Control 0.035766 (SMAD1), transcript variant 1 BC039337.1 IOH62273 Polyadenylate-binding protein- Control 0.035766 interacting protein 2 NM_001950.3 IOH23241 E2F transcription factor 4, Control 0.035766 p107/p130-binding (E2F4) BC008819.1 IOH6323 nuclear receptor subfamily 1, Control 0.035766 group H, member 3 (NR1H3) NM_024818.1 IOH9860 ubiquitin-activating enzyme E1- Control 0.035766 domain containing 1 (UBE1DC1), transcript variant 1 NM_004838.2 IOH12410 homer homolog 3 (Drosophila) Control 0.035766 (HOMER3) NM_012419.3 IOH11052 regulator of G-protein signaling 17 Control 0.035766 (RGS17) BC042999.2 IOH25869 Putative Polycomb group protein Control 0.035766 ASXL2 NM_005441.2 IOH13577 chromatin assembly factor 1, Control 0.035766 subunit B (p60) (CHAF1B) BC009055.1 IOH3376 Protein FAM184A Control 0.035766 BC006818.1 IOH3186 1-acylglycerol-3-phosphate O- Control 0.035766 acyltransferase 1 (lysophosphatidic acid acyltransferase, alpha), mRNA (cDNA clone IMAGE: 3448169), complete cds. BC053509.1 IOH29394 5,10-methylenetetrahydrofolate Control 0.035766 reductase (NADPH) (MTHFR) BC051888.1 IOH27068 tRNA-yW synthesizing protein 1 Control 0.035766 homolog (S. cerevisiae) (TYW1) NM_001952.2 IOH6989 E2F transcription factor 6 (E2F6) Control 0.035766 PV3871 dual-specificity tyrosine-(Y)- Control 0.035766 phosphorylation regulated kinase 4 (DYRK4) BC012746.1 IOH14565 mesoderm development candidate Control 0.035766 2 (MESDC2) NM_003341.3 IOH43236 Ubiquitin-conjugating enzyme E2 Control 0.035766 E1 NM_138499.2 IOH40143 PWWP domain-containing protein Control 0.035766 2B NM_032051.1 IOH13231 POZ (BTB) and AT hook Control 0.035766 containing zinc finger 1 (PATZ1), transcript variant 4 BC007565.1 IOH6820 phospholipase C, gamma 2 Control 0.035766 (phosphatidylinositol-specific) (PLCG2) NM_022083.1 IOH45531 Protein Niban Control 0.035766 NM_052940.3 IOH10671 leucine rich repeat containing 42 Control 0.035766 (LRRC42) BC044884.1 IOH26494 KIAA0265 protein (KIAA0265) Control 0.035766 BC000452.1 IOH3518 peroxiredoxin 2 (PRDX2) Control 0.035766 NM_018246.1 IOH40864 coiled-coil domain containing 25 Control 0.035766 (CCDC25) BC005033.1 IOH6631 actinin, alpha 4 (ACTN4) Control 0.035766 BC000583.1 IOH22887 Thimet oligopeptidase Control 0.035766 NM_006406.1 IOH7551 peroxiredoxin 4 (PRDX4) Control 0.035766 BC034488.2 IOH22312 ATP-binding cassette, sub-family Control 0.035766 F (GCN20), member 1 (ABCF1) BC020942.1 IOH11137 transmembrane protein 140 Control 0.035766 (TMEM140) NM_003223.1 IOH9646 transcription factor AP-4 Control 0.035766 (activating enhancer binding protein 4) (TFAP4) BC011863.2 IOH14833 DNA helicase HEL308 (HEL308) Control 0.035766 NM_025057.1 IOH35314 chromosome 14 open reading Control 0.035766 frame 45 (C14orf45) NM_031361.1 IOH4674 collagen, type IV, alpha 3 Control 0.035766 (Goodpasture antigen) binding protein (COL4A3BP), transcript variant 2 NM_052965.1 IOH56031 tRNA-splicing endonuclease Control 0.035766 subunit Sen15 NM_199334.2 IOH6734 thyroid hormone receptor, alpha AD 0.037822 (erythroblastic leukemia viral (v- erb-a) oncogene homolog, avian) (THRA), transcript variant 1 NM_201567.1 IOH37812 cell division cycle 25 homolog A AD 0.037822 (S. pombe) (CDC25A), transcript variant 2 BC012945.1 IOH25802 Uncharacterized protein C19orf57 AD 0.038115 NM_005663.2 IOH46152 Wolf-Hirschhorn syndrome Control 0.038115 candidate 2 (WHSC2) BC025266.1 IOH23199 taspase, threonine aspartase, 1 Control 0.038169 (TASP1) NM_014487.2 IOH4416 zinc finger protein 330 (ZNF330) Control 0.038169 NM_197957.2 IOH41003 MYC associated factor X (MAX), Control 0.038169 transcript variant 6 NM_006695.2 IOH5798 RUN domain containing 3A Control 0.038169 (RUNDC3A) NM_144594.1 IOH10942 family with sequence similarity Control 0.038169 112, member B (FAM112B) NM_032146.2 IOH10608 ADP-ribosylation factor-like 6 Control 0.038169 (ARL6), transcript variant 1 BC014218.2 IOH12802 THAP domain-containing protein 3 Control 0.038169 BC037845.1 IOH62213 Multiple coagulation factor Control 0.038169 deficiency protein 2 BC043394.1 IOH26350 ankyrin repeat domain 17 AD 0.040087 (ANKRD17) NM_053005.2 IOH40119 HCCA2 protein (HCCA2) AD 0.040087 NM_175065.2 IOH35055 histone cluster 2, H2ab AD 0.040087 (HIST2H2AB) NM_004706.3 IOH45526 Rho guanine nucleotide exchange AD 0.040087 factor (GEF) 1 (ARHGEF1), transcript variant 2 NM_014346.1 IOH22792 TBC1 domain family, member AD 0.040087 22A (TBC1D22A) NM_133480.1 IOH13139 transcriptional adaptor 3 (NGG1 AD 0.040118 homolog, yeast)-like (TADA3L), transcript variant 2 BC002448.2 IOH4300 actin binding LIM protein 1 Control 0.041317 (ABLIM1) BC048969.1 IOH26897 TSPY-like 1 (TSPYL1) AD 0.041317 NM_020319.1 IOH27320 ankyrin repeat and MYND domain AD 0.041317 containing 2 (ANKMY2) NM_016046.2 IOH11580 exosome component 1 (EXOSC1) AD 0.042299 NM_001003396.1 IOH3597 tumor protein D52-like 1 AD 0.042315 (TPD52L1), transcript variant 3 NM_005870.3 IOH53845 Histone deacetylase complex AD 0.042315 subunit SAP18 NM_003403.3 IOH27684 YY1 transcription factor (YY1) AD 0.042315 BC036096.2 IOH27280 zinc finger protein 18 (ZNF18) AD 0.042315 NM_001010844.1 IOH43230 Interleukin-1 receptor-associated AD 0.043024 kinase 1-binding protein 1 BC029524.1 IOH22562 Coiled-coil domain-containing AD 0.04393 protein 46 NM_005884.2 IOH2475 p21(CDKN1A)-activated kinase 4 Control 0.04393 (PAK4), transcript variant 1 NM_033642.1 IOH36760 fibroblast growth factor 13 Control 0.045355 (FGF13), transcript variant 1B BC058900.1 IOH29076 rabaptin, RAB GTPase binding Control 0.045355 effector protein 2 (RABEP2) BC015239.1 IOH10789 zinc finger and BTB domain Control 0.045355 containing 8 (ZBTB8) NM_001005339.1 IOH13018 regulator of G-protein signaling 10 Control 0.045355 (RGS10), transcript variant 1 NM_006819.1 IOH5061 stress-induced-phosphoprotein 1 Control 0.045355 (Hsp70/Hsp90-organizing protein) (STIP1) NM_152387.2 IOH53987 BTB/POZ domain-containing AD 0.045355 protein KCTD18 BC002369.1 Serine/threonine-protein kinase AD 0.045355 PLK1 BC092404.1 IOH62574 Rap guanine nucleotide exchange AD 0.045786 factor 3 NM_004922.2 IOH38664 SEC24 related gene family, AD 0.046722 member C (S. cerevisiae) (SEC24C), transcript variant 1 NM_198217.1 IOH59743 Inhibitor of growth protein 1 AD 0.046722 BC051911.1 IOH27047 chromosome 13 open reading AD 0.046722 frame 24 (C13orf24) NM_006205.1 IOH40356 phosphodiesterase 6H, cGMP- AD 0.046722 specific, cone, gamma (PDE6H) NM_024790.2 IOH13277 centrosome and spindle pole Control 0.046828 associated protein 1 (CSPP1), transcript variant 2 NM_006439.3 IOH12221 Protein mab-21-like 2 AD 0.046828 NM_173456.1 IOH45493 phosphodiesterase 8A (PDE8A), AD 0.048209 transcript variant 4 BC019268.1 IOH13177 Protein arginine N- AD 0.048209 methyltransferase 1 NM_173642.1 IOH26158 family with sequence similarity AD 0.048209 80, member A (FAM80A) NM_194299.1 IOH35431 Synaptonemal complex protein 2- AD 0.048209 like BC062323.1 IOH40678 chromosome 21 open reading AD 0.048209 frame 25 (C21orf25) NM_021709.1 IOH21450 Apoptosis regulatory protein Siva AD 0.048209 BC100813.1 IOH63506 Putative T-complex protein 1 AD 0.048209 subunit theta-like 2 BC026317.1 IOH11060 solute carrier family 16, member 1 AD 0.048209 (monocarboxylic acid transporter 1) (SLC16A1) BC010956.1 IOH13684 Keratinocyte growth factor AD 0.048209 NM_005034.2 IOH10479 polymerase (RNA) II (DNA AD 0.048209 directed) polypeptide K, 7.0 kDa (POLR2K) BC024291.1 IOH14775 BR serine/threonine kinase 2 AD 0.048209 (BRSK2) NM_001001568.1 IOH53504 phosphodiesterase 9A (PDE9A), AD 0.048209 transcript variant 3, mRNA. NM_014314.3 IOH52971 Probable ATP-dependent RNA AD 0.048209 helicase DDX58 BC047420.1 IOH26512 UBX domain-containing protein 7 AD 0.048209 NM_000430.2 IOH39940 platelet-activating factor AD 0.048209 acetylhydrolase, isoform Ib, alpha subunit 45 kDa (PAFAH1B1) PV3873 epidermal growth factor receptor AD 0.048209 (erythroblastic leukemia viral (v- erb-b) oncogene homolog, avian) (EGFR); see catalog number for detailed information on wild-type or point mutant status NM_001328.1 IOH12818 C-terminal binding protein 1 AD 0.048209 (CTBP1), transcript variant 1 NM_001009959.1 IOH43447 Ermin AD 0.048209 BC050387.1 IOH26653 ankyrin repeat and sterile alpha AD 0.048209 motif domain containing 3 (ANKS3) NM_007194.1 Serine/threonine-protein kinase AD 0.048209 Chk2 NM_018492.2 IOH12390 PDZ binding kinase (PBK) AD 0.048209 NM_182801.1 IOH23237 EGF-like, fibronectin type III and AD 0.048209 laminin G domains (EGFLAM), transcript variant 4 BC016615.1 IOH10688 RAB37, member RAS oncogene AD 0.048209 family (RAB37) BC008950.2 IOH56909 Prenylated Rab acceptor protein 1 AD 0.048209 BC041831.1 IOH27713 transducin-like enhancer of split 3 AD 0.048209 (E(sp1) homolog, Drosophila) (TLE3) NM_003104.2 IOH14671 sorbitol dehydrogenase (SORD) AD 0.048209 BC003555.1 IOH4980 nucleolar complex associated 2 AD 0.048209 homolog (S. cerevisiae) (NOC2L) NM_001274.2 CHK1 checkpoint homolog (S. pombe) AD 0.048209 (CHEK1) NM_153645.1 IOH11663 nucleoporin 50 kDa (NUP50), AD 0.048209 transcript variant 3 BC017423.1 IOH12806 mesoderm induction early AD 0.048209 response 1 homolog (Xenopus laevis) (MIER1) BC007424.2 IOH6160 PRP4 pre-mRNA processing AD 0.048209 factor 4 homolog (yeast) (PRPF4) NM_007107.2 IOH13133 signal sequence receptor, gamma AD 0.048209 (translocon-associated protein gamma) (SSR3) XM_096472.2 IOH42996 hypothetical LOC143678 AD 0.048209 (LOC143678) NM_015698.2 IOH3563 G patch domain and KOW motifs AD 0.048209 (GPKOW) NM_018111.1 IOH57283 Putative uncharacterized protein AD 0.048209 FLJ10490 NM_006694.1 IOH2941 jumping translocation breakpoint AD 0.048209 (JTB) NM_000045.2 IOH14233 arginase, liver (ARG1) AD 0.048209 BC074765.2 IOH59064 POU domain, class 6, transcription AD 0.048209 factor 1 NM_172028.1 IOH42497 ankyrin repeat and BTB (POZ) AD 0.048209 domain containing 1 (ABTB1), transcript variant 3 BC026345.1 IOH10790 Ermin AD 0.048209 NM_201262.1 IOH41260 DnaJ (Hsp40) homolog, subfamily AD 0.048209 C, member 12 (DNAJC12), transcript variant 2 NM_002966.1 IOH14651 S100 calcium binding protein A10 AD 0.048209 (S100A10) BC013352.1 IOH14736 HpaII tiny fragments locus 9c AD 0.048209 protein NM_004873.1 IOH26366 BCL2-associated athanogene 5 AD 0.048209 (BAG5), transcript variant 2 BC009415.1 IOH14115 kinesin family member 26A AD 0.048209 (KIF26A) BC012539.1 IOH12758 mediator complex subunit 31 AD 0.048209 (MED31) BC021247.1 IOH22996 Phosphatase and actin regulator 4 AD 0.048209 NM_004414.3 IOH5722 regulator of calcineurin 1 AD 0.048209 (RCAN1), transcript variant 1 BC028840.1 IOH13887 ankyrin repeat domain 13C AD 0.048209 (ANKRD13C) BC025787.1 IOH12000 alkB, alkylation repair homolog 1 AD 0.048209 (E. coli) (ALKBH1) NM_000459.1 Angiopoietin-1 receptor AD 0.048209 NM_000788.1 IOH42066 Deoxycytidine kinase AD 0.048209 NM_173859.1 IOH35196 breast cancer and salivary gland AD 0.048209 expression gene (RP11-49G10.8) NM_152382.1 IOH39899 JmjC domain-containing protein AD 0.048209 C2orf60 NM_002038.2 IOH14517 interferon, alpha-inducible protein AD 0.048209 6 (IFI6), transcript variant 1 BC034984.1 IOH26875 Kinesin-like protein KIF16B AD 0.048209 NM_014582.1 IOH40248 odorant binding protein 2A AD 0.048209 (OBP2A) BC057760.1 IOH29220 MORN repeat-containing protein 3 AD 0.048209 NM_005595.1 IOH12791 nuclear factor I/A (NFIA) AD 0.048209 NM_032726.1 IOH21106 phospholipase C, delta 4 (PLCD4) AD 0.048209 NM_153276.1 IOH21851 solute carrier family 22 (organic AD 0.048209 anion transporter), member 6 (SLC22A6), transcript variant 2 NM_001011538.1 IOH39826 similar to 60S ribosomal protein AD 0.048209 L21 (LOC402176) NM_006433.2 IOH27865 granulysin (GNLY), transcript AD 0.048209 variant NKG5 NM_024800.1 Serine/threonine-protein kinase AD 0.048209 Nek11 NM_015850.2 Basic fibroblast growth factor AD 0.048209 receptor 1 NM_006590.2 IOH45672 ubiquitin specific peptidase 39 AD 0.048209 (USP39) NM_199054.1 IOH37765 MAP kinase interacting AD 0.048209 serine/threonine kinase 2 (MKNK2), transcript variant 2 BC050696.1 IOH27004 chromosome 12 open reading AD 0.048209 frame 48 (C12orf48) NM_024563.1 IOH23059 chromosome 5 open reading frame AD 0.048209 23 (C5orf23) NM_004832.1 IOH4381 glutathione S-transferase omega 1 AD 0.048209 (GSTO1) NM_003242.2 transforming growth factor, beta AD 0.048209 receptor II (70/80 kDa) (TGFBR2), transcript variant 2 BC050444.1 IOH26738 golgi autoantigen, golgin AD 0.048209 subfamily a, 4 (GOLGA4) NM_201259.1 IOH45586 Mitochondrial import inner AD 0.048209 membrane translocase subunit TIM14 NM_032124.3 IOH27146 haloacid dehalogenase-like AD 0.048209 hydrolase domain containing 2 (HDHD2) NM_002870.1 IOH3059 RAB13, member RAS oncogene AD 0.048209 family (RAB13) BC000337.2 IOH3577 glucose-6-phosphate AD 0.048209 dehydrogenase (G6PD) BC060785.1 IOH29158 tripartite motif-containing 40 AD 0.048209 (TRIM40) BC030597.1 IOH22318 ATR interacting protein (TREX1) AD 0.048209 BC050551.1 IOH26948 BCL2-associated athanogene 5 AD 0.048209 (BAG5) NM_004697.3 IOH12861 PRP4 pre-mRNA processing AD 0.048209 factor 4 homolog (yeast) (PRPF4) NM_020990.2 IOH5022 creatine kinase, mitochondrial 1B AD 0.048209 (CKMT1B), nuclear gene encoding mitochondrial protein BC039742.1 IOH26173 poly(rC) binding protein 1 AD 0.048209 (PCBP1) BC021573.1 IOH14848 GTP-binding protein 10 AD 0.048209 NM_015068.1 IOH27074 paternally expressed 10 (PEG10), AD 0.048209 transcript variant 1 NM_001827.1 IOH5978 CDC28 protein kinase regulatory AD 0.048209 subunit 2 (CKS2) NM_152876.1 IOH50154 Tumor necrosis factor receptor AD 0.048209 superfamily member 6 BC015548.1 IOH10351 RAB3A interacting protein AD 0.048209 (rabin3) (RAB3IP) BC062359.1 IOH40676 chromosome 8 open reading frame AD 0.048209 47 (C8orf47) BC029424.1 IOH23140 Probable glutathione peroxidase 8 AD 0.048209 NM_001786.2 IOH14583 cell division cycle 2, G1 to S and AD 0.048209 G2 to M (CDC2), transcript variant 1 BC000870.1 IOH3246 TIMELESS interacting protein AD 0.048209 (TIPIN) NM_004103.2 Protein tyrosine kinase 2 beta AD 0.048209 BC022454.2 IOH10977 Transient receptor potential cation AD 0.048209 channel subfamily M member 3 NM_024046.1 IOH21132 CaM kinase-like vesicle- AD 0.048209 associated (CAMKV) BC040521.1 IOH27477 testis expressed 2 (TEX2) AD 0.048209 BC003164.1 IOH46140 leukocyte receptor cluster (LRC) AD 0.048209 member 4 (LENG4) NM_000402.2 IOH2390 Glucose-6-phosphate 1- AD 0.048209 dehydrogenase BC069328.1 IOH40255 Bcl2 modifying factor (BMF) AD 0.048209 BC063463.1 IOH39865 coenzyme Q3 homolog, AD 0.048209 methyltransferase (S. cerevisiae) (COQ3) NM_000572.2 IOH29878 Interleukin-10 AD 0.048209 NM_006374.2 serine/threonine kinase 25 (STE20 AD 0.048209 homolog, yeast) (STK25) NM_017966.1 IOH5829 vacuolar protein sorting 37 AD 0.048209 homolog C (S. cerevisiae) (VPS37C) BC052602.1 IOH29373 carbonic anhydrase XIII (CA13) AD 0.048209 BC018063.1 IOH10722 potassium channel tetramerisation AD 0.048209 domain containing 4 (KCTD4) NM_031305.1 IOH38124 Rho GTPase activating protein 24 AD 0.048209 (ARHGAP24), transcript variant 2 BC056401.1 IOH28794 centaurin, delta 2 (CENTD2) AD 0.048209 BC022459.1 IOH11064 sulfotransferase family 4A, AD 0.048209 member 1 (SULT4A1) XM_373630.2 IOH41531 PREDICTED: Homo sapiens AD 0.048209 hypothetical protein LOC145842 (LOC145842) P3049 v-abl Abelson murine leukemia AD 0.048209 viral oncogene homolog 1 (ABL1), transcript variant a; see catalog number for detailed information on wild-type or point mutant status NM_153012.1 IOH12147 Tumor necrosis factor ligand AD 0.048209 superfamily member 12 NM_018270.3 IOH14702 MRG-binding protein AD 0.048209 BC010739.1 IOH9887 COP9 signalosome complex AD 0.048209 subunit 7b NM_015002.2 IOH42260 F-box protein 21 (FBXO21), AD 0.048209 transcript variant 2 BC000497.1 CaM kinase-like vesicle- AD 0.048209 associated protein NM_001449.2 IOH13860 four and a half LIM domains 1 AD 0.048209 (FHL1) BC065912.1 IOH40442 Tyrosine-protein kinase ABL2 AD 0.048209 NM_153356.1 IOH27369 TBC1 domain family, member 21 AD 0.048209 (TBC1D21) BC032382.1 IOH21661 similar to pleckstrin homology AD 0.048209 domain containing, family M (with RUN domain) member 1; adapter protein 162, mRNA, complete cds. BC094800.1 IOH62619 Jouberin AD 0.048362 NM_207035.1 IOH41684 UPF0471 protein C1orf63 Control 0.048362 homolog NM_003897.2 IOH6603 immediate early response 3 (IER3) AD 0.048717 NM_178821.1 IOH22298 WD repeat domain 69 (WDR69) AD 0.048717 NM_198219.1 IOH59467 Inhibitor of growth protein 1 AD 0.048717 NM_024805.1 IOH13501 chromosome 18 open reading AD 0.048717 frame 22 (C18orf22) NM_001040633.1 IOH61663 protein kinase, AMP-activated, AD 0.048717 gamma 2 non-catalytic subunit (PRKAG2), transcript variant c, mRNA. NM_130807.1 IOH10112 MOB1, Mps One Binder kinase AD 0.049919 activator-like 2A (yeast) (MOBKL2A) BC008623.1 IOH3309 roundabout, axon guidance AD 0.049919 receptor, homolog 3 (Drosophila) (ROBO3) NM_001004285.1 IOH45460 DNA fragmentation factor, 40 kDa, AD 0.049919 beta polypeptide (caspase- activated DNase) (DFFB), transcript variant 3 BC011885.1 IOH14206 eukaryotic translation initiation AD 0.049919 factor 2A, 65 kDa (EIF2A)

Using a small subset of the identified indicators, it was possible to diagnose AD with great efficiency. The twenty protein microarray fluorescence values depicted in Table 4 were used to classify blinded samples as either Alzheimer's or control. A threshold value was calculated for each diagnostic indicator using the following equation:

Diagnostic Threshold=[(Mean AD Fluorescence Value)−(Mean Control Fluorescence Value)/2]+(Mean Control Fluorescence Value)

A fluorescence value for any given diagnostic indicator over the threshold value for that indicator is scored as a positive result. Using the antigens from Table 4, greater than or equal to four positive results out of the possible twenty diagnostic indicators predicts with high accuracy that the sample is from an Alzheimer's Disease patient. Less than four positive results out of the possible twenty diagnostic indicators on Table 4 predicts with high accuracy that the sample is from a healthy Control. (See Drawing) Initial results with this diagnostic logic were as follows:

Alzheimer's Disease (AD) vs. All Controls

(Using twenty biomarkers from Table 4)

(See Drawing)

-   N=90 (50 AD, 40 Control) -   Overall Error Rate: 4.44%

Predicted/True AD Control AD 50 4 Control 0 36 Error Rate 0.000 0.010

EXAMPLE 9 Diagnosis of Alzheimer's Disease

Twenty antibodies and their respective antigens were selected that were rated as highly significant by multiple statistical analysis programs (Prospector, PAM, Random Forest) and performed well in a single platform. The antibodies are listed in Table 8.

TABLE 8 Diagnostic Autoantibodies in Alzheimer's Disease MW Database ID #: Name: (kDa): Indication: Reactivity: BC051695.1 FRMD8 51.2 Alzheimer's ↑ AD, ↓CON NM_015833.1 ADARB1 80.8 Alzheimer's ↑ AD, ↓CON NM_002305.2 LGALS1 14.7 Alzheimer's ↑ AD, ↓CON NM_001641.2 APEX1 35.6 Alzheimer's ↑ AD, ↓CON NM_024316.1 LENG1 30.5 Control ↓ AD, ↑CON NM_014280.1 DnaJ 29.8 Alzheimer's ↑ AD, ↓CON homolog subfamily C member 8 PHC1244 CCL19 11.0 Alzheimer's ↑ AD, ↓CON BC064984.1 ASXL1 9.5 Alzheimer's ↑ AD, ↓CON NM_021104.1 RPL41 3.4 Alzheimer's ↑ AD, ↓CON BC004236.2 UBE2S 23.9 Alzheimer's ↑ AD, ↓CON NM_012387.1 PADI4 74.1 Alzheimer's ↑ AD, ↓CON NM_003384.1 VRK1 45.5 Alzheimer's ↑ AD, ↓CON NM_004113.3 FGF12 27.4 Alzheimer's ↑ AD, ↓CON BC021174.1 Small 12.4 Alzheimer's ↑ AD, ↓CON EDRK- rich factor 1 NM_001001794.1 FAM116B 66.5 Alzheimer's ↑ AD, ↓CON NM_032377.2 ELOF1 9.5 Alzheimer's ↑ AD, ↓CON NM_024754.2 PTCD2 43.9 Alzheimer's ↑ AD, ↓CON NM_000984.2 RPL23A 17.7 Alzheimer's ↑ AD, ↓CON NM_139016.2 C20orf198 Alzheimer's ↑ AD, ↓CON NM_024668.1 ANKHD1 269.5 Alzheimer's ↑ AD, ↓CON

With these twenty biomarkers (listed in Table 4 and Table 8) and the simple diagnostic logic explained above, it was possible to differentiate Alzheimer's Disease serum samples from Control serum samples with over 95% efficiency.

It is also possible to accurately diagnose using only the four biomarkers from Table 3. Diagnostic efficiency for these diagnostic indicators was assessed for AD, low Mini-Mental Status Examination (MMSE) AD and high-MMSE AD. The results are shown below.

Alzheimer's Disease (AD) vs. All Controls

Random Forest:

-   N=90 (50 AD, 40 Control) -   Overall Error Rate: 7.78%

Predicted/True AD Control AD 48 5 Control 2 35 Error Rate 0.040 0.125

-   Predictive Analysis ofMicroarrays (PAM): -   N=90 (50 AD, 40 Con) -   Overall Error Rate: 7.8%

Predicted/True AD Control AD 50 7 Control 0 33 Error Rate 0.000 0.175 Low-MMSE AD vs. All Controls

(Low-MMSE AD samples have MMSE <15)

-   Random Forest: -   N=55 (15 Low-MMSE AD, 40 Control) -   Overall Error Rate: 7.26%

Predicted/True AD Control AD 13 2 Control 2 38 Error Rate 0.133 0.050

-   Predictive Analysis ofMicroarrays (PAM): -   N=30 (15 Low-MMSE AD, 15 Control) -   Overall Error Rate: 9.9%

Predicted/True AD Control AD 13 1 Control 2 14 Error Rate 0.133 0.067 High-MMSE AD vs. All Controls

(High-MMSE AD samples have MMSE >15)

-   Random Forest: -   N=75 (35 High-MMSE AD, 40 Control) -   Overall Error Rate: 10.67%

Predicted/True AD Control AD 32 5 Control 3 35 Error Rate 0.086 0.125

-   Predictive Analysis ofMicroarrays (PAM): -   N=70 (35 High-MMSE AD, 35 Control) -   Overall Error Rate: 12.8%

Predicted/True AD Control AD 28 2 Control 7 33 Error Rate 0.200 0.057

Using a combination of the biomarkers listed in Tables 3 and 5 (totaling nine diagnostic indicators), the efficiency of distinction between AD and Parkinson's Disease was also assessed. The results are shown below.

Alzheimer's Disease (AD) vs. Parkinson's Disease (PK)

-   Random Forest: -   N=79 (29 AD, 29 PK) -   Overall Error Rate: 12.07%

Predicted/True AD PK AD 25 3 PK 4 26 Error Rate 0.138 0.103

-   Predictive Analysis ofMicroarrays (PAM): -   N=58 (29 AD, 29 PK) -   Overall Error Rate: 12.0%

Predicted/True AD PK AD 24 2 PK 5 27 Error Rate 0.172 0.069

It was determined that it was possible to differentiate AD and control with over 95% accuracy using the twenty antigens from Table 4 and over 90% accuracy using the four antigens on Table 3, however, the use of only these four indicators did not allow accurate differentiation of Alzheimer's Disease from other neurodegenerative diseases like Parkinson's Disease. Accurate differentiation requires the inclusion of antigens from Table 5. In practice, however, this distinction is often unnecessary, since patients presenting with suspected Alzheimer's disease come with memory and cognitive deficits, whereas patients with early Parkinson's most often show tremors with no complaints of cognitive and/or memory deficits.

EXAMPLE 10 Diagnosis of Alzheimer's Disease Ethics Statement

Approval for the use of blood samples for this study was obtained from the UMDNJ-Stratford Institutional Review Board.

Patient Samples

Serum samples from 50 AD subjects and 40 non-demented controls (NDC) were obtained from Analytical Biological Systems, Inc. (Wilmington, Del.). 30 breast cancer (BC) serum samples and 29 Parkinson's disease (PD) serum samples were obtained from Asterand, Inc. (Detroit, Mich.). To represent different disease stages reflecting disease severity, the AD serum pool contained samples with Mini-Mental State Examination (MMSE) scores ranging from 2-24. All samples were handled by standard procedures and stored at −80° C. Diagnosis of AD was based on a medical evaluation, neuropsychiatric testing, and on the National Institute of Neurological and Communicative Disorders and the Alzheimer's Disease and Related Disorders Association criteria. Demographic characteristics of the study population are shown in Table 9.

TABLE 9 Demographics of Serum Donors Age Sex Group n Mean Range (% male) MMSE Alzheimer's disease 50 78.5 61-97 40% 2-24 Earlier-stage¹ 35 78.7 61-97 43% 15-24 Later-stage² 15 78.0 65-94 33% 2-14 Non-demented Controls 40 40.4 19-86 82% — Older Control 20 57.7 51-86 100%  — Younger Control 20 24.7 19-30 65% — Parkinson's disease 29 74.0 53-88 55% — Breast Cancer 30 46.7 32-54  0% — ¹Earlier-stage: AD patients with WSE ≥ 15 ²Later-stage: AD patients with WSE < 15

Human Protein Microarrays

To identify autoantibodies in human sera, Invitrogen's ProtoArray v5.0 Human Protein Microarrays (Cat. No. PAH0525020, Invitrogen, Carlsbad, Calif., USA), each containing 9,486 unique human protein antigens (wwwdotinvitrogendotcom/protoarray) were used. All proteins had been expressed as GST fusion proteins in insect cells, purified under native conditions, and spotted in duplicate onto nitrocellulose-coated glass slides. All arrays were probed and scanned according to the manufacturer's instructions using commercially prepared reagents. Briefly, microarray slides were blocked (Blocking Buffer, Cat. No. PA055,Invitrogen) and then incubated with serum samples, diluted 1:500 in washing buffer. After washing, the arrays were probed with anti-human IgG (H+L) conjugated to AlexaFluor 647 (Cat. No. A-21445, Invitrogen). Arrays were then washed, dried, and immediately scanned with a GenePix 4000B Fluorescence Scanner (Molecular Devices, Sunnyvale, Calif., USA).

Dot Blot Analysis

One μl volumes of purified recombinant human FRMD8 (0.2 μg/μl) and PTCD2 (0.1 μg/μl) proteins (Cat. No. TP307879 and TP315253, OriGene Technologies, Inc., Rockville, Md., USA), were manually pipetted onto a nitrocellulose membrane. The proteins were blocked in a 5% non-fat milk PBS-Tween solution for one hour at room temperature (RT). The proteins were then probed with human serum samples diluted 1:2000 for one hour at RT. All sera were identical to those used to probe the human protein microarrays. The dot blots were probed with an anti-human IgG (H+L) HRP conjugate antibody (Cat. No. 31410, Thermo Fisher Scientific Inc., Pittsburgh, Pa., USA) for one hour at RT, incubated with ECL reagent (Cat. No. 34096, Thermo Fisher Scientific Inc., Pittsburgh, Pa., USA) for one minute, and then exposed to X-ray film at various intervals.

Data Analysis

The fluorescence data for each microarray was acquired by Genepix Pro analysis software after scanning, and then synced with Invitrogen's lot-specific Genepix Array List (GAL) files. The resulting Genepix Results (GPR) files were then imported into Invitrogen's Prospector 5.2 for analysis. All data was MIAME compliant and the raw data has been deposited in a MIAME compliant database. The “group characterization” and “two-group comparison” features in the IRBP Toolbox allowed for M-statistical analysis of autoantibody expression. Sorting detectable autoantibodies by difference of prevalence between AD and NDC groups in descending order, the top 10 were selected as potential diagnostic biomarkers.

The selected biomarkers were re-verified as significant by Predictive Analysis for Microarrays (PAM)—an independent algorithm relying on nearest shrunken centroid analysis to identify proteins acting as significant class-differentiators. The predictive classification accuracy of the identified biomarkers was tested with Random Forest (RF) using the default settings, another significance algorithm run as an R package (v 2.12.1). In RF, partitioning trees were built by successively splitting the samples according to a measure of statistical impurity at a given node until terminal nodes are as homogenous as possible. Classification accuracy for a given set of diagnostic biomarkers was reported in a confusion matrix and misclassification as an Out-Of-Bag (00B) error score.

Results

Protein Microarrays Reveal that Autoantibodies are Numerous in Human Serum

To detect autoantibodies in sera, protein microarrays were probed with individual serum samples (n=149) (Table 9). Results using the standard Chebyshev Inequality p-value threshold of 0.05 suggested an average of over one thousand different autoantibodies per serum sample; although the number varied widely from one individual to the next (n=149, 1115±1096) (Table 10).

TABLE 10 Estimate of Autoantibodies Per Sample Group Sample Group (n) Median σ Range All Samples 149  920 1096  0-6389 Alzheimer's disease 50 969.25 770  0-3311 Earlier-stage 35 826.5 672  0-2805 Later-stage 15 1321.5 865 110-3311 Non-demented 40 982 965  0-3585 controls Older Controls 20 1066.25 896 32-2675  Younger Controls 20 942.5 1050 0-3585 Parkinson's disease 29 539.5 762 0-2585 Breast Cancer 30 884.5 1723 5-6389

Selection of Autoantibody Biomarkers for AD Diagnosis

A total of 90 human serum samples (50 AD and 40 NDC) were randomly assigned to either a Training or Testing Set composed of 25 AD and 20 NDC sera each; both containing equal proportions of earlier- and later-stage AD samples as well as older and younger controls. To identify potential diagnostic autoantibodies protein microarrays, each containing 9,486 antigens, were probed with Training Set sera and the data was analyzed as described above. Prospector analysis software determined that 451 autoantibodies had a significantly higher prevalence in the AD group than in the NDC group (p<0.01). The 10 biomarkers that demonstrated the largest difference in group prevalence between AD and NDC were selected to serve as diagnostic indicators. As an independent verification of the 10 biomarkers selected, Predictive Analysis for Microarrays (PAM) was utilized. PAM confirmed that the 10 biomarkers originally selected by Prospector were among the most significant classifiers of AD and NDC. The ten biomarkers are shown in Table 11.

TABLE 11 Identity and Significance of 10 AD vs. NDC Diagnostic Biomarkers Prevalence Prevalence Database ID Description in AD in Control p NM_024754.2 Pentatricopeptide 94.23% 14.29% 8.03E−14 repeat domain 2 (PTCD2) BC051695.1 FERM domain 73.08%  4.76% 4.06E−13 containing 8 (FRMD8) NM_018956.2 Chromosome 9 open 82.69% 14.29% 3.30E−09 reading frame 9 (C9orf9) NM_002305.2 Lectin, galactoside- 65.39%  9.52% 3.76E−08 binding, soluble, 1 (galectin 1) (LGALS1) NM_000939.1 Proopiomelanocortin 65.39% 11.91% 1.18E−05 (adrenocorticotropin/ beta-lipotropin/ alpha-melanocyte stimulating hormone/beta- melanocyte stimulating hormone/beta- endorphin) (POMC), transcript variant 2 NM_003668.2 Mitogen-activated 71.15% 11.91% 8.91E−09 protein kinase- activated protein kinase 5 (MAPKAPK5), transcript variant 1 BC033758.1 Centaurin, alpha 2 82.69% 23.81% 5.27E−08 (CENTA2) NM_014280.1 DnaJ homolog 78.85% 11.91% 9.49E−12 subfamily C member 8 NM_024668.2 Ankyrin repeat 73.08% 14.29% 1.05E−06 and KH domain containing 1 (ANKHD1), transcript variant 3 NM_023937.1 Mitochondrial 73.08% 16.67% 3.15E−05 ribosomal protein L34 (MRPL34), nuclear gene encoding mitochondrial protein

Verification of Biomarkers via Training and Testing Set Analyses

To assess the Training and Testing set classification accuracies of the 10 selected biomarkers, Random Forest (RF) was used. RF is a statistical algorithm which creates voting classes of decision-making trees to evaluate the significance of each marker and classify samples and is described by Breiman (2001), Machine Learning 45: 5-32. Using the 10 biomarkers to “diagnose” the Training Set (n=45; 25 AD and 20 NDC), RF had an overall accuracy of greater than 93% [Out-of-Bag (00B) Error 6.67%, a positive predictive value (PPV) of 92.3%, and a negative predictive value (NPV) of 94.7%]. When the 10 biomarkers were used to classify the Testing Set sera (n=45; 25 AD and 20 NDC), which played no part in the biomarker selection process, RF distinguished AD samples from NDCs with a similar accuracy (prediction error of 6.67%, PPV of 100.0%, and NPV of 87.0%).

Biomarker Performance in Different Sample Demographics

When the 10 autoantibody biomarkers were used to classify all AD and NDC samples combined (n=90; 50 AD, 40 NDC) using RF, they did so with a 96.0% sensitivity and 92.5% specificity. Their performance in classifying samples from different demographics: earlier-stage AD, later-stage AD, older controls, and younger controls was also tested. The 10 biomarkers classified samples with over 90% accuracy in all subgroups tested (Table 12). AD samples were correctly differentiated from younger controls with high and consistent accuracy, a common-sense indication of biomarker credibility.

TABLE 12 Diagnostic Accuracies of Selected Biomarkers Earlier-stage Later-stage AD (n = 50) vs. AD (n = 35) vs. AD (n = 15) vs. All Older Younger PD Breast All Older All Older NDC Control Control * Cancer NDC Control NDC Control n = 40 n = 20 n = 20 n = 29 n = 30 n = 40 n = 20 n = 40 n = 20 Sensitivity % 96.0 98.0 98.0 90.0 98.0 97.1 97.1 86.7 93.3 Specificity % 92.5 85.0 90.0 79.3 83.0 92.5 90.0 97.5 90 PPV % 94.1 94.2 96.1 88.2 90.7 91.9 94.4 92.9 87.5 NPV % 94.9 94.4 94.7 82.1 96.2 97.4 94.7 95.1 94.7 * The biomarkers used for this classification are those of Table 13; all others are the biomarkers identified in Table 11. Distinction of AD from Other Diseases

The ability of the biomarker diagnostic to differentiate AD from other non-neurological and neurological diseases was assessed. 30 breast cancer serum samples were acquired and the 10 selected diagnostic biomarkers were used to differentiate them from the 50 AD samples. RF reported an OOB Error of 7.5% (PPV and NPV of 90.7% and 96.2%, respectively). These results are similar to those of the AD versus NDC trials above and demonstrate no diagnostic bias toward general disease.

The ability of the biomarker diagnostic to differentiate between two closely related neurodegenerative diseases was also assessed. For this, Parkinson's disease (PD)was selected because it shares much in common with Alzheimer's pathology. There is also a significant overlap (22%˜48%) at the pathological and clinical levels, making it difficult to clearly distinguish these two diseases by conventional means alone. Again, Prospector, PAM, and RF were utilized to identify the most significant disease classifiers. It was determined that by using only five diagnostic biomarkers (Table 13), it was possible to differentiate AD samples from PD samples with over 86% accuracy (sensitivity=90.0%, specificity=79.3%).

TABLE 13 Identity and Significance of Five AD vs. PD Diagnostic Biomarkers Prevalence Prevalence Database ID Description in AD in PD p BC051695.1 FERM domain  9.62% 45.16% 5.93E−04 containing 8 (FRMD8) NM_003177.3 Spleen tyrosine 19.23% 70.97% 1.35E−05 kinase (SYK) BC019015.2 Mediator complex  9.62% 61.29% 1.61E−06 subunit 29 (MED29) BC003551.1 Transglutaminase 2 (C 13.46% 61.29% 9.67E−05 polypeptide, protein- glutamine-gamma- glutamyltransferase) (TGM2) BC001755.1 Leiomodin-1 26.92% 70.97% 6.84E−05

Dot Blot Confirmation of Potential Biomarkers

To further validate the differential expression of autoantibodies detected with human protein microarrays, a comparative dot-blot analysis using commercially-obtained, purified native proteins was performed. Two of the most potent differentiating antigens identified, PTCD2 and FRMD8, were selected and their reactivity was verified. The two proteins were spotted onto nitrocellulose membrane and probed with identical sera to that used on the microarrays. Results from both AD and NDC sera show strong agreement in the relative intensities of the immunoreaction in protein microarrays and dot blots. The majority of AD sera reacted intensely to purified PTCD2 and FRMD8 protein, while most control sera showed a weak or no reaction. Dot blot assays independently confirmed that anti-FRMD8 and anti-PTCD2 antibodies were more predominant in AD sera than in NDC sera.

All references cited herein are incorporated by reference herein in their entireties. 

What is claimed:
 1. A method of detecting neurodegenerative disease diagnostic autoantibodies in a subject, the method comprising: (a) obtaining an immunoglobulin-containing biological sample from the subject, and (b) performing an assay to determine the presence or absence of autoantibodies in the biological sample, wherein the assay comprises: (i) contacting the biological sample with at least two autoantigens selected from the group consisting of cDNA clone MGC:31944 IMAGE:4878869; cDNA clone MGC:27152 IMAGE:4691630; and hematopoietic SH2 domain-containing protein (HSH2D), under conditions that allow immunocomplexes of each of the at least two autoantigens and a corresponding autoantibody to form; and (ii) detecting the presence or absence of the corresponding immunocomplexes in the biological sample.
 2. The method of claim 1, wherein the neurodegenerative disease comprises at least one selected from the group consisting of Alzheimer's Disease, Parkinson's Disease, and vascular dementia.
 3. The method of claim 1, wherein the assay in (b) further comprises: contacting the biological sample with at least one additional autoantigen selected from the group consisting of cDNA clone MGC:32654 IMAGE:4701898 and cleavage and polyadenylation specific factor 3, 73 kDa (CPSF3), under conditions that allow immunocomplexes of each of the at least one additional autoantigen and a corresponding autoantibody to form; and detecting the presence or absence of the corresponding immunocomplexes in the biological sample.
 4. The method of claim 1, wherein the biological sample is selected from the group consisting of whole blood, serum, cerebrospinal fluid, saliva, and sputum.
 5. The method of claim 1, wherein the autoantigens are attached to a substrate.
 6. The method of claim 5, wherein the autoantigens are in the form of an array.
 7. The method of claim 6, wherein the array is a microarray.
 8. The method of claim 5, wherein the substrate is a bead or a nitrocellulose-coated glass slide.
 9. A method of identifying a subject as having, or being at risk for having, a neurodegenerative disease, the method comprising (a) obtaining an immunoglobulin-containing biological sample from the subject, (b) performing an assay to determine the presence or absence of autoantibodies in the biological sample, wherein the assay comprises: (i) contacting the biological sample with at least two autoantigens selected from the group consisting of cDNA clone MGC:31944 IMAGE:4878869; cDNA clone MGC:27152 IMAGE:4691630; and hematopoietic SH2 domain-containing protein (HSH2D), under conditions that allow immunocomplexes of each of the at least two autoantigens and a corresponding autoantibody to form; and (ii) detecting the presence or absence of the immunocomplexes in the biological sample, wherein, if autoantibodies to the at least two autoantigens are present in the biological sample, the subject is identified as having, or being at risk for having, at least one neurodegenerative disease selected from the group consisting of Alzheimer's Disease, Parkinson's Disease, and vascular dementia.
 10. The method of claim 9, wherein, if the subject is identified as having, or being at risk for having, the at least one neurodegenerative disease, the subject is further treated for the at least one neurodegenerative disease.
 11. The method of claim 9, wherein the assay in (b) further comprises: contacting the biological sample with at least one additional autoantigen selected from the group consisting of cDNA clone MGC:32654 IMAGE:4701898 and cleavage and polyadenylation specific factor 3, 73kDa (CPSF3), under conditions that allow immunocomplexes of each of the at least one additional autoantigen and a corresponding autoantibody to form; and detecting the presence or absence of the corresponding immunocomplexes in the biological sample, and wherein, if the autoantibody/antibodies to the at least one additional autoantigen is/are further present in the biological sample, the subject is identified as having, or being at risk for having, at least one neurodegenerative disease selected from the group consisting of Alzheimer's Disease, Parkinson's Disease, and vascular dementia.
 12. The method of claim 9, wherein the biological sample is selected from the group consisting of whole blood, serum, cerebrospinal fluid, saliva, and sputum.
 13. The method of claim 9, wherein the autoantigens are attached to a substrate.
 14. The method of claim 9, wherein the autoantigens are in the form of an array.
 15. The method of claim 14, wherein the array is a microarray.
 16. The method of claim 13, wherein the substrate is a bead or a nitrocellulose-coated glass slide.
 17. A method of generating a subject-specific, neurodegenerative disease-specific autoantibody profile, the method comprising: (a) obtaining an immunoglobulin-containing biological sample from a subject, (b) performing an assay to determine the presence or absence of autoantibodies in the biological sample, wherein the assay comprises: (i) contacting the biological sample with at least two autoantigens selected from the group consisting of cDNA clone MGC:31944 IMAGE:4878869; cDNA clone MGC:27152 IMAGE:4691630; and hematopoietic SH2 domain-containing protein (HSH2D), under conditions that allow immunocomplexes of each of the at least two autoantigens and a corresponding autoantibody to form; and (ii) detecting the presence or absence of the immunocomplexes in the biological sample; and (c) generating a subject-specific neurodegenerative disease-specific autoantibody profile of the disease diagnostic autoantibodies present in the biological sample.
 18. An ordered microarray comprising a substrate and autoantigens immobilized onto the substrate, wherein the only autoantigens in the microarray are the following: a first group of autoantigens consisting of Pentatricopeptide repeat domain 2 (PTCD2); FERM domain containing 8 (FRMD8); Chromosome 9 open reading frame 9 (C9orf9); Lectin, galactoside-binding, soluble, 1 (galectin 1) (LGALS1); Proopiomelanocortin (adrenocorticotropin/beta-lipotropin/alpha-melanocyte stimulating hormone/beta-melanocyte stimulating hormone/beta-endorphin) (POMC), transcript variant 2; Mitogen-activated protein kinase-activated protein kinase 5 (MAPKAPKS), transcript variant 1; Centaurin, alpha 2 (CENTA2); DnaJ homolog subfamily C member 8; Ankyrin repeat and KH domain containing 1 (ANKHD1), transcript variant 3; Mitochondrial ribosomal protein L34 (MRPL34), and nuclear gene encoding mitochondrial protein; and a second group of two or more autoantigens selected from the group consisting of hematopoietic SH2 domain containing (HSH2D); proteins corresponding to cDNA clone MGC:27152 IMAGE:4691630, complete cds; cDNA clone MGC:31944 IMAGE:4878869, complete cds; and cDNA clone MGC:32654 IMAGE:4701898, complete cds.
 19. The ordered microarray of claim 18, wherein two or more autoantigens from the second group are selected from the group consisting of cDNA clone MGC:31944 IMAGE:4878869, complete cds; hematopoietic SH2 domain containing (HSH2D); and cDNA clone MGC:32654 IMAGE:4701898, complete cds.
 20. The ordered microarray of claim 18, wherein the substrate is a bead or a nitrocellulose-coated glass slide. 